AU738452B2 - Integrin receptor antagonists - Google Patents

Abstract

The present invention relates to compounds and derivatives thereof, their synthesis, and their use as integrin receptor antagonists. More particularly, the compounds of the present invention are antagonists of the integrin receptors alpha nu beta 3, alpha nu beta 5, and/or alpha nu beta 6 and are useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, wound healing, viral disease, tumor growth, and metastasis.

Description

Integrin Receptor Antagonists Field of the Invention The present invention relates to compounds and derivatives thereof, their synthesis, and their use as integrin receptor antagonists. More particularly, the compounds of the present s invention are antagonists of the integrin receptors cavp3, avp5, and/or av36 and are useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, wound healing, viral disease, tumour growth, and metastasis.

Background of the Invention to It is believed that a wide variety of disease states and conditions can be mediated by acting on integrin receptors and that integrin receptor antagonists represent a useful class of drugs.

Integrin receptors are heterodimeric transmembrane proteins through which cells attach and communicate with extracellular matrices and other cells (See S.B. Rodan and G.A. Rodan, "Integrin Function In Osteoclasts", Journal of Endocrinology, Vol. 154, S47-S56 (1997), which is i 15 incorporated by reference herein in its entirety).

In one aspect of the present invention, the compounds herein are useful for inhibiting bone I. resorption. Bone resorption is mediated by the action of cells known as osteoclasts. Osteoclasts are large multinucleated cells of up to about 400mm in diameter that resorb mineralised tissue, chiefly calcium carbonate and calcium phosphate, in vertebrates. Osteoclasts are actively motile 20 cells that migrate alone the surface of bone, and can bind to bone, secrete necessary acids and [R:\LIBAA]08974.doc:sak WO 99/30713 PCT/US98/26485 proteases, thereby causing the actual resorption of mineralized tissue from the bone. More specifically, osteoclasts are believed to exist in at least two physiological states, namely, the secretory state and the migratory or motile state. In the secretory state, osteoclasts are flat, attach to the bone matrix via a tight attachment zone (sealing zone), become highly polarized, form a ruffled border, and secrete lysosomal enzymes and protons to resorb bone. The adhesion of osteoclasts to bone surfaces is an important initial step in bone resorption. In the migratory or motile state, the osteoclasts migrate across bone matrix and do not take part in resorption until they again attach to bone.

Integrins are involved in osteoclast attachment, activation and migration. The most abundant integrin in osteoclasts, in rat, chicken, mouse'and human osteoclasts, is an integrin receptor known as avp3, which is thought to interact in bone with matrix proteins that contain the RGD sequence. Antibodies to avp3 block bone resorption in vitro indicating that this integrin plays a key role in the resorptive process. There is increasing evidence to suggest that avp3 ligands can be used effectively to inhibit osteoclast mediated bone resorption in vivo in mammals.

The current major bone diseases of public concern are osteoporosis, hypercalcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, immobilizationinduced osteopenia, and glucocorticoid-induced osteoporosis. All of these conditions are characterized by bone loss, resulting from an imbalance between bone resorption, i.e. breakdown, and bone formation, which continues throughout life at the rate of about 14% per year on the average. However, the rate of bone turnover differs from site to site; for example, it is higher in the trabecular bone of the vertebrae and the alveolar bone in the jaws than in the cortices of the long bones. The potential for bone loss is directly related to turnover and can amount to over 5% per year in vertebrae immediately following menopause, a condition which leads to increased fracture risk.

In the United States, there are currently about 20 million people with detectable fractures of the vertebrae due to osteoporosis. In -2- WO 99/30713 PCT/US98/26485 addition, there are about 250,000 hip fractures per year attributed to osteoporosis. This clinical situation is associated with a 12% mortality rate within the first two years, while 30% of the patients require nursing home care after the fracture.

Individuals suffering from all the conditions listed above would benefit from treatment with agents which inhibit bone resorption.

Additionally, avp3 ligands have been found to be useful in treating and/or inhibiting restenosis, i.e. recurrence of stenosis after corrective surgery on the heart valve, atherosclerosis, diabetic retinopathy, macular degeneration, and angiogenesis, i.e. formation of new blood vessels. Moreover, it has been postulated that the growth of tumors depends on an adequate blood supply, which in turn is dependent on the growth of new vessels into the tumor; thus, inhibition of angiogenesis can cause tumor regression in animal models (See Harrison's Principles of Internal Medicine, 12th ed., 1991, which is incorporated by reference herein in its entirety). Therefore, avp3 antagonists which inhibit angiogenesis can be useful in the treatment of cancer by inhibiting tumor growth (See Brooks et al., Cell, 79:1157- 1164 (1994), which is incorporated by reference herein in its entirety).

Moreover, compounds of this invention can also inhibit neovascularization by acting as antagonists of the integrin receptor, A monoclonal antibody for avp5 has been shown to inhibit VEGFinduced angiogenesis in rabbit cornea and the chick chorioallantoic membrane model (See M.C. Friedlander, et al., Science 270, 1500-1502, (1995), which is incorporated by reference herein in its entirety). Thus, compounds that antagonize avp5 are useful for treating and preventing macular degeneration, diabetic retinopathy, tumor growth, and metastasis.

Additionally, compounds of the instant invention can inhibit angiogenesis and inflammation by acting as antagonists of the integrin receptor, av36, which is expressed during the later stages of wound healing and remains expressed until the wound is closed (See Christofidou-Solomidou, et al., "Expression and Function of Endothelial Cell av Integrin Receptors in Wound-Induced Human Angiogenesis in Human Skin/SCID Mice Chimeras, American Journal of Pathology, -3- WO 99/30713 PCT/US98/26485 Vol. 151, No. 4, pp. 975-983 (October 1997), which is incorporated by reference herein in its entirety). It is postulated that avp6 plays a role in the remodeling of the vasculature during the later stages of angiogenesis. Also, avp6 participates in the modulation of epithelial inflammation and is induced in response to local injury or inflammation (See Xiao-Zhu Huang, et al., "Inactivation of the Integrin 36 Subunit Gene Reveals a Role of Epithelial Integrins in Regulating Inflammation in the Lungs and Skin," Journal of Cell Biology, Vol. 133, No.4, pp. 921-928 (May 1996), which is incorporated by reference herein in its entirety). Accordingly, compounds that antagonize avp6 are useful in treating or preventing cancer by inhibiting tumor growth and metastasis.

In'addition, certain compounds of this invention antagonize both the av33 and av5 receptors. These compounds, referred to as "dual avp3/av5 antagonists," are useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, tumor growth, and metastasis.

In addition, certain compounds of this invention are useful as mixed avp3, avp5, and av36 receptor antagonists.

It is therefore an object of the present invention to provide compounds which are useful as integrin receptor antagonists.

It is another object of the present invention to provide compounds which are useful as avp3 receptor antagonists.

It is another object of the present invention to provide compounds which are useful as avp5 receptor antagonists.

It is another object of the present invention to provide compounds which are useful as avp6 receptor antagonists.

It is another object of the present invention to provide compounds which are useful as dual cav3/avp5 receptor antagonists.

It is another object of the present invention to provide compounds which are useful as mixed av33, avp5, and avp6 receptor antagonists.

It is another object of the present invention to provide pharmaceutical compositions comprising integrin receptor antagonists.

-4- It is another object of the present invention to provide methods for making the pharmaceutical compositions of the present invention.

It is another object of the present invention to provide methods for eliciting an integrin receptor antagonising effect in a mammal in need thereof by administering the compounds and pharmaceutical compositions of the present invention.

It is another object of the present invention to provide compounds and pharmaceutical compositions useful for inhibiting bone resorption, restenosis, atherosclerosis, inflammation, viral disease, diabetic retinopathy, macular degeneration, angiogenesis, tumour growth, and metastasis.

It is another object of the present invention to provide compounds and pharmaceutical o1 compositions useful for treating osteoporosis.

It is another object of the present invention to provide methods for inhibiting bone resorption, restenosis, atherosclerosis, inflammation, viral disease, diabetic retinopathy, macular degeneration, angiogenesis, tumour growth, and metastasis.

It is another object of the present invention to provide methods for treating osteoporosis.

These and other objects will become readily apparent from the detailed description which follows.

999*9 Summary of the Invention The present invention relates to compounds of the formula W-X-Y-Z C0 2

R

9 20 wherein W is selected from the group consisting of

R

0 N N N rN H H H

R

1

R

1 NN NN N H and H X is

-(CH

2 wherein any methylene (CH 2 carbon atom is either unsubstituted or substituted with one or two R 1 substituents; Y is selected from the group consisting of -(CH2)m-, [R:\L[BAA]08974.doc:sak

-(CH

2 )m-O-(CH 2

-(CH

2 )m-NR 4

-(CH

2 -(0H 2 )mS-(0H 2

-(H

2 )m-S0-(0H 2 -(0H 2 )m-S02-(CH 2 -(CH2)m-O-(CH2)n-O-(CH2)p-, -(0H2)m0-(CH2)n-NR 4 -(CH2)p-, -(CH2)m-NR 4 -(CH2)n-NR 4

-(CH

2 -(0H2)m0O-(0H2)n-S-(0H2)p-, -(CH2)m-S-(CH2)n-S-(CH2)p-, -(CH2)m-NR4-(CH 2 )n-S-(CH 2 -(CH2)m-NR 4 -(CH2)n-O-(CH2)p-, (CH2)-S-(0H2)n-O-(0H2)p-, and

(CH

2 )mS(CH 2 )n-NR 4

-(CH

2 wherein any methylene (CH2) carbon atom in Y, other than in R 4 can be substituted by one or two R3 substituents; Z is 0 10R10 R R HN /ll *N Ny Ny 00 0 10 0 Ny and 0

R

1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, Ci-jo alkyl, 03-8 cycloalkyl, C3-8 cycloheteroalkyl, 03-8 cycloalkyl C1-6 alkyl, C3-8 cycloheteroalkyl C1- alkyl, aryl, aryl 0148 alkyl, amino, amino C1-8 alkyl, C1-3 acylamino, 01.3 acylamino C1-8 alkyl, (0146 alkyl)pamino, (0146 alkyl)pamino 01-8 alkyl, Ci-4 alkoxy, ClA alkoxy 01-6 alkyl, hydroxycarbonyl, hyd roxycarbonyl 01.6 alkyl, 01.3 alkoxycarbonyl, 01.3 alkoxycarbonyl 01.6 alkyl, hydroxycarbonyl- [R:\LIBAA]08974.doc:sak Ci-6 alkyloxy, hydroxy, hydroxy 0146 alkyl, C1-6 alkyloxy- 0146 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, 01-8 alkyl-S(O)p, (C1-8 alkyI)paminocarbonyl,

C

1 -8 alkyloxycarbonylamino, (0148 alkyl)paminocarbonyloxy, (aryl 0148 alkyI)pamino, (aryI)pamino, aryl 0148 alkylsulfonylamino, and 0148 alkylsulfonylamino; or two R 1 substituents, when on the same carbon atom, are taken together with the carbon atom to which they are attached to form a carbonyl group; each R 3 is independently selected from the group consisting of hydrogen, aryl, Ci-ic alkyl, '*~:aryl-(CH2),O-(0H 2 aryl-(CH 2 )rS(O)p-(CH 2 aryl-(CH2),N(R 4 2 aryl-(0H2),N (R 4

)-(CH

2 halogen, hydroxyl, oxo, trifluoromethyl, 01-8 alkylcarbonylamino, aryl C1-5 alkoxy, 01.5 alkoxycarbonyl, (0148 alkyl)paminocarbonyl, C1-6 alkylcarbonyloxy, 03-8 cycloalkyl, (0146 alkyl)pamino, amino Ci.6 alkyl, arylaminocarbonyl, aryl C1.5 alkylaminocarbonyl, aminocarbonyl, RAL>\aminocarbonyl 01-6 alkyl, r 35 hyd roxycarbonyl, [R:\LIBAA]08974.doc:sak hydroxycarbonyl 01.6 alkyl, 01.6 alky-0=-C-(CH2)t-, 03-7 cycloalkyI-0=-O-(CH2)t-, aryI-0=-C-(CH2)t-, 01.6 alkylary=-C0-(0H2)t-,

CH

2 =OH-(0H 2 01.6 alkyl-OH=CH-(CH2)t-, 03.7 cycloalkyl-OH=CH-(0H 2 10 aryl-CH=CH-(CH2)r-, 01.6 alkylaryl-OH=CH-(0H2)t-, 01.6 alkyl-S02-(CH2)t-, S* 01.6 alkylaryl-S02-(CH2)t-, 01.6 alkoxy, i arylCl-6 alkoxy, aryl 01-6 alkyl, alkyl)pamino C-6 alkyl, (aryI)pamino, (aryI)pamino 01.6 alkyl, 00se 20 (aryl 01.6 alkyI)pamino, (aryl 01.6 alkyI)pamino 01.6 alkyl, arylcarbonyloxy, aryl 01.6 alkylcarbonyloxy, (01.6 alkyI)paminocarbonyloxy, 01.8 alkylsuylfonylamino, arylsu Ifonylamino, Ci.8 alkylsulfonylamino 01.6 alkyl, arylsulfonylamino 01.6 alkyl, ary l 16 alkylsulfonylamino, aryl 01.6 alkylsulfonylamino 01.6 alkyl, 01.8 alkoxycarbonylamino, 01.8 alkoxycarbonylamino 01.8 alkyl, aryloxycarbonylamino C1-8 alkyl, r RA4,, I arylOCl- alkoxycarbonylamino, 35 4aryl 01.8 alkoxycarbonylamino 01.8 alkyl, [R\LI BAA]08974. doe: sak Cl-8 alkylcarbonylamino, Ci-s al kylcarbonyl amino Cl- alkyl, arylcarbonylamino Ci-6 alkyl, aryl 0 i- aikylcarbonylamino, aryl Cl- alkylcarbonylamino C 1 alkyl, amninocarbonylamnino Ci- alkyl, (Ci- alkyl)paminocarbonylamino, (0i- alkyl)paminocarbonylamino Ci- alkyl, (aryl)paminocarbonylamino CI- alkyl, (aryl Cl- alkyi)paminocarbonylamino, .(aryl 0 i- alkyl)paminocarbonylamino 01-6 alkyl, :amninosuifonylamnino Ci- alkyl, (0i- alkyI)paminosulfonylamino, (0i- alkyl)paminosulfonylamino Ci- alkyl, (aryl) pamninosulfonylamnino C1- alkyl, (aryl 0 i- alkyl) paminosulfonylamino, (aryl 0 i- alkyl) paminosulfonylamino 01-6 alkyl, 0 i- alkylsulfonyl, 2C -16 alkylsulfonyl Cl- alkyl, arylsulfonyl C1-6 alkyl, ::aryl Cl- alkylsulfonyl, aryl C 1 alkylsulfonyl Ci-6 alkyl, Cl- alkylcarbonyl, Cl- alkylcarbonyl C1-6 alkyl, arylcarbonyl Ci- alkyl, aryl C1. alkylcarbonyl, aryl Ci- alkylcarbonyl C1-6 alkyl, 0 i- alkylth iocarbon yl amino, 01-6 al kylth iocarbon yl amino 01-6 alkyl, arylthiocarbonylamnino 0. alkyl, aryl 01.6 alkyithiocarbonylamino, aryl C1- alkylthiocarbonylamnino 01-6 alkyl, ~(Ci-8 alkyI)paminocarbony Cl-6 alkyl, '2 11 (aryl)paminocarbonyl C1. alkyl, Lji (aryl 0148 alkyI)paminocarbonyI, and [R:\LIBAA]08974.doc:sak (aryl Ci-8 alkyI)paminocarbonyI C 1 -6 alkyl; or two R 3 substituents, when on the same carbon atom are taken together with the carbon atom to which they are attached to form a carbonyl group or a cyclopropyl group, wherein any of the alkyl groups of R 3 are either unsubstituted or substituted with one to three R 1 substituents, and provided that each R 3 is selected such that in the resultant compound the carbon atom or atoms to which R 3 is attached is itself attached to no more than one heteroatom; each R 4 is independently selected from the group consisting of hydrogen, aryl, aminocarbonyl,

C

38 cycloalkyl, amino C1-6 alkyl, (aryl)paminocarbonyl, (aryl 01.5 alkyl)paminocarbonyl, hydroxycarbonyl Ci- alkyl, C1- alkyl, aryl C1- alkyl, *ly~aio 26akl (ary1-6 alkyl)amino C2 alkyl, C1- alkylsulfonyl, 01-8 alkoxycarbonyl, aryloxycarbonyl, aryl C1- alkoxycarbonyl, C1- alkylcarbonyl, arylcarbonyl, aryl 0i- alkylcarbonyl, (Ci- alkyl)paminocarbonyl, aminosu Ifonyl, C1- alkylaminosulfonyl, (aryl)paminosulfonyl, (aryl C1- alkyl)paminosulfonyl, arylsulfonyl, RA/~N\aryl C1- alkylsulfonyl, Ci-6C alkylthiocarbonyl, S 35 cLh} arylthiocarbonyl, and [R:\LIBAA]08974.doc:sak aryl Ci-6 alkylthiocarbonyl, wherein any of the alkyl groups of R 4 are either unsubstituted or substituted with one to three R' substituents;

R

5 and R 6 are each independently selected from the group consisting of hydrogen, Ci-io alkyl, aryl, aryl-(CH2)rO-(CH2)s,-, aryl-(CH2)rS(O)p-(CH2)s-, aryl-(0H2)r0C(O)-(0H2)s-, aryl-(CH2)r-(N (R 4

)-(CH

2 halogen, hydroxyl, 0148 alkylcarbonylamino, aryl 01.5 alkoxy, alkoxycarbonyl, (014 alkyl)paminocarbonyl, Ci- alkylcarbonyloxy, ::C3-8 cycloalkyl, (0146 alkyl)pamino, amino 01-6 alkyl, arylaminocarbonyl, aryl C1.5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl alkyl, hydroxycarbonyl, hydroxycarbonyl C1.6 alkyl,

HC=-C-(CH

2 0146 alkyl-C=-C-(CH2)t-, 03-7 cycloalkyl-C=-0-(CH2)t-, MA/ aryl-C=-C-(CH2)t-, 1 014 alkylaryl-0=-0-(0H2)t-, T 35)Li CH20CH-(0H2)r, [R:\LIBAA]08974.doc:sak 01-6 alkyl-CH=CH-(CH 2 0 3.7 cycloalkyl-CH=CH-(0H 2 aryt-CH=CH-(CH2)r-, 0 i- alkylaryl-CH=CH-(0H 2 Ci- alkyl-S02-(CH2)t-, Cv-6 alkylaryl-S02-(CH2)t-, Ci- alkoxy, aryl Ci- alkoxy, aryl Cl- alkyl, (Ci- alkyI)pamino 01-6 alkyl, (aryI)pamino, (aryI)pamino 0 i- alkyl, (aryl Ci- alkyI)pamino, :(aryl Ci- alkyI)pamino Ci- alkyl, arylcarbonyloxy, aryl 0 i- alkylcarbonyloxy, (01-6 alkyl)paminocarbonyloxy, *Ci- alkylsuylfonylamino, arylsu Ifonylamino, Ci- alkylsulfonylamino Ci- alkyl, :arylsulfonylamino C1- alkyl, aryl Cl- alkyisulfonylamino, aryl Ci- alkylsulfonylamino C1- alkyl, Ci- alkoxycarbonylamino, Ci- alkoxycarbonylamino Cl- alkyl, aryloxycarbonylamino Ci.8 alkyl, aryl Ci- alkoxycarbonylamino, aryl Ci- alkoxycarbonylamino Ci- alkyl, Cl- alkylcarbonylamino, Ci-8 alkylcarbonylamino Ci- alkyl, arylcarbonylamino Cl- alkyl, aryl Cl- alkylcarbonylamino, aryl Ci- alkylcarbonylamino C1.6 alkyl, aminocarbonylamino C1. alkyl, (Ci-8 alkyl)paminocarbonylamino, W NT [R:\LIBAA]08974.doc:sak (0i- alkyI)paminocarbonylamino 01-6 alkyl, (aryl)paminocarbonylamino 01-6 alkyl, (aryl C1- alkyI)paminocarbonylamino, (aryl Ci- alkyI)paminocarbonylamino 0i- alkyl, aminosulfonmylamino C 1 alkyl, (Ci-8 alkyI)paminosulfonylamino, 0 i- alkyI)paminosulfonylamino C 1 alkyl, (aryl)paminosulfonylamino C 1 alkyl, (aryl C1-8 alkyI)paminosulfonylamino, (aryl 01-8 alkyl) paminosulfonylamino 01-6 alkyl, C1-6 alkylsulfonyl, *Ci- alkylsulfonyl Ci- alkyl, arylsulfonyl Ci-6 alkyl, aryl C1- alkylsulfonyl, aryl 01-6 alkylsulfonyl Ci- alkyl, 01.6 alkylcarbonyl, C1-6 alkylcarbonyl 01-6 alkyl, arylcarbonyl C1-6 alkyl, aryl C1- alkylcarbonyl, aryl C0- alkylcarbonyl 01-6 alkyl, :C1-6 alkylthiocarbonylamino, C1- .lyticroyamn i6akl 0iarlythiocarbonylamino Ci alkyl, arylth1-6carboyloainCkyln, ~aryl C1- alkyithiocarbonylaminoC- akl aryl Oi alkyltiocarbonylamino6 alkyl, (01ayl)paminocarbonyl i alkyl, (arylIC-ainoca o Oalkoyl,an (aryl CO-8 alkyl)paminocarbonyl I, a yl o~(ry R5 adyR6 ainotake n ogehe aihteabnatkyl;ihteyaeatahdtofr cab0y or upadR, r ae tgte ihtecronao owihte aeatce ofr caron ayo h lyl group fR n 6aeete nusittdo usiue ihoet three RI substituents, and provided that each R 5 and R 6 are selected such that in the resultant ~RA~mpound the carbon atom to which R 5 and R 6 are attached is itself attached to no more than one Jjb teroatom; [R:\LIBAA]08974.doc:sak

R

7 and R 8 are each independently selected from the group consisting of hydrogen, Ci-jo alkyl, aryl, aryl-(CH2)r-O-(0H 2 aryl-(CH2)r-S(O)p-(CH 2 aryl-(CH2)~Nr)-C(O)-(CH 2 aryl-(0H2)r-(N(R 4 2)s-, halogen, :hydroxyl, C1- alkylcarbonylamino, aryl C 15 alkoxy, 01-5 alkoxycarbonyl, (0i- alkyI)paminocarbonyl, Ci- alkylcarbonyloxy, 9C3- cycloalkyl, 20(Cl- alkyl)pamino, amino 01-6 alkyl, arylaminocarbonyl, aryl CI- alkylaminocarbonyl, aminocarbonyl, aminocarbonyl C1- alkyl, hydroxycarbonyl, hydroxycarbonyl CI- alkyl, HC=-C-(CH2)r-, C1- alkyl-C=-C-(CH2)t-, C3-7 cycloalkyl-C=-C-(CH2)r-, aryl-C=-C-(CH2)t-, C1- alkylaryl-C=-C-(CH2)t-, 0H2=CH-(CH2)t-, C1- alkyl-CH=CH-(CH 2

RA

1 C3-7 cycloalkyl-CH=CH-(CH2)t-, aryl-CH=CH-(CH2)t-, [R:\LIBAA]08974.doc:sak Cl-6 alkylaryl-CH=CH-(0H2)r-, C1-6 alkyla-S02-(CH2)t-, Ci-6 alkoxy, aryl Ci-6 alkoxy, aryl Cl-6 alkyl, (aryI)pamino, (aryI)pamino Ci-6 alkyl, (aryl Ci-6 alkyI)pamino, aryl C6arboylxy, o i6 lkl arylCikicarbonyloxy, (Ci-6 alkyI)paminocarbonyloxy, Ci-8 alkylsuylfonylamino, arylcarbonylamino, arylsu Ifonylamino, Cl-8 alkylsulfonylamnino C1-6 alkyl, arylsulfonylamnino Cl-6 alkyl, aryl Cl-6 alkylsulfonylamino, aryl 01.6 alkylsulfonylamino Ci-6 alkyl, Cl.

8 alkoxycarbonylamino, Cl-8 alkoxycarbonylamnino C1-8 alkyl, aryloxycarbonylamnino Cl-8 alkyl, aryl 01-8 al koxycarbonyl amino, aryl C1-8 al koxycarbonyl amino C1-8 alkyl, Ci- alkylcarbonylamino, 0148 alkylcarbonylamino 01.6 alkyl, arylcarbonylamino C1-6 alkyl, aryl Ci-6 alkylcarbonylamino, aryl 01.6 alkylcarbonylamino 01.6 alkyl, amninocarbonylamnino 01.6 alkyl, arylaminocarbonylamino, (1-8 alky)paminocarbonylamino, 3 5 (Ci-8 alkyl)paminocarbonylamino 01.6 alkyl, [R:\LIBAA]08974.doc:sak (ar yl)paminocarbonylamino C 1 -6alkyl, (aryl 01.6 alkyI)paminocarbonylamino, (aryl 01.6 alkyI)paminocarbonylamino 01-6 alkyl, aminosulfonmylamino C01 alkyl, (Cl-8alkyl)paminosulfonylamino, (01.6 alkyl)paminosulfonylamino Ci-6alkyl, (aryI)paminosulfonylamino 01 6alkyl, (aryl Ci.6 alkyI)paminosulfonylamino, (aryl Ci-8alkyl) paminosulfonylamino 01-6 alkyl, 10 01-6 alkylsulfonyl, 01 6alkylsulfonyl 01-6 alkyl, 000.*:arylsulfonyl C01 alkyl, 0 0 0 aryl C01 alkylsulfonyl, 0. 0 aryl 01.6alkylsulfonyl C01 alkyl, 01-6 alkylcarbonyl, 1akylcarbonyl 01-6 alkyl, aryl 01-6 alkylcarbonyl, 00. aryl 01-6 alkylcarbonyl Ci-6 alkyl, 20 Cl-6alkylthiocarbonylamino, 01alkylthiocarbonylamino01.6 alkyl, 60.* aryithiocarbonylamino Oi 6alkyl, aryl 01.6 alkylthiocarbonylamino, aryl Ci-6alkyithiocarbonylamino Ov-6alkyl, (014 alkyl)paminocarbonyl 01-6 alkyl, (aryI)paminocarbonyl 01.6 alkyl, (aryl 014 alkyI)paminocarbonyl, (ary l-86alkyI)paminocarbonyl I i6 alkyl, and 0720 polycycyl 004 alkylsulfonylamino; wherein any of the alkyl groups of R 7 and R 8 are either unsubstituted or substituted with one to three R 1 substituents, and provided that each R 7 and R 8 are selected such that in the resultant compound the carbon atom to which R 7 and W 8 are attached is itself attached to no more than one heteroatom;

RA~

1

R

9 is selected from the group consisting of hydrogen, [RALIBAA]08974.doc:sak 01.8 alkyl, aryl, aryl C1-8 alkyl, 01-8 alkylcarbonyloxy C14 alkyl, aryl 01.8 alkylcarbonyloxy Oils alkyl, 01-8 alkylaminocarbonylmethylene, and 01-8 dialkylaminocarbonylmethylene;

R

1 0

R

1 1

R

12 and R 13 are each independently selected from the group consisting of hydrogen, 10 01.8 alkyl, aryl, halogen, hydroxyl, oxo' aminocarbonyl,

C

3 -8 cycloalkyl, amino 01.6 alkyl, (aryl)paminocarbonyl, hydroxycarbonyl, :20 (aryl 01-5 alkyl)paminocarbonyl, :hydroxycarbonyl 01.8 alkyl, aryl 01.6 alkyl, (01.6 alkyl)pamino C1-6 alkyl, (aryl C1-6 alkyl)pamino 02-6 alkyl, 01.8 alkylsulfonyl, 01.8 alkoxycarbonyl, aryloxycarbonyl, aryl 01.8 alkoxycarbonyl, 01.8 alkylcarbonyl, arylcarbonyl, aryl 01.8 alkylcarbonyl, (01.8 alkyl)paminocarbonyl, SRA4-> aminosulfonyl, 01-8 alkylaminosulfonyl, (aryl)paminosulfonyl, [R:\LIBAA]08974.doc:sak (aryl Ci-8 alkyl)paminosulfonyI, Cl-6 aikylsulfonyl, a ryls uIf onyl, aryl C 1 -6 alkylsulfonyl, aryl Ci-6 alkylcarbonyl, Ci- alkyithiocarbonyl, aryithiocarbonyl, aryl 0i- alkyithiocarbonyl, aryl-(CH2)r-O-(0H2)s-, 10 aryl-(CH2)r-S(O)p-(CH 2 aryl-(CH 2 )r-C(O)N)-(CH 2 arl( H )rC H aryl-(CH 2

),N(R

4 2 01aryI-C2,CR-(CH2)-, 153-Cyco- kCCH) aky-C C3- cyalkyly-C=-C-(CH2)t, 20 C=-C-(0H2)r-, 0000 Ci-6 alkyla-C=C-(0H2)t, 030 Cy2Cloy-(CH H-(02)- Claryl-CH=CH-(H 2 C3-7 cyalkyl-CH=CH-(CH 2 1-akyl-S02C-(CH2), Cli alkylaryl-S02C-(CH2)r, Cl- alkylcarbonylamino, aryl 01.5 alkoxycarbonyl, (Cl- alkyI)paminocarbonyI, Cl- alkylcarbonyloxy, (01.6 alkyl)pamino, aminocarbonyl C1- alkyl, Cl016 alkoxy, aryl alkoxy, R:LI BAA]08974.doc: sak 19 (aryI)pamino, (aryI)pamino C 1 alkyl, (aryl 0 i- alkyi)pamino, (aryl 01-6 alkyl)pamino Ci- alkyl, arylcarbonyloxy, aryl C 1 alkyicarbonyloxy, (01.6 alkyl)paminocarbonyloxy, Ci-8 alkylsulfonylamino, a rylsuIf on ylamino, Cl-8 alkylsulfonylamnino 01-6 alkyl, :arylsulfonylamnino Ci- alkyl, aryl Ci-6 alkylsulfonylamino, aryl Cl- alkylsulfonylamnino Ci-6 alkyl, Cl- alkoxycarbonylamino, Cl- alkoxycarbonylamnino C 1 alkyl, aryloxycarbonylamino C1-8 alkyl, ary .l8akxcroyaio aryl 01- alkoxycarbonylamnino 01-8 alkyl, 01-8 alkylcarbonylamino, :20 Ob-8 alkylcarbonylamino Ci-6alkyI, arylcarbonylamino 01.6 alkyl, ary l 16 alkylcarbonylamino, aryl 01.6 alkyicarbonylamino 01-6 alkyl, amninocarbonylamnino 01.6 alkyl, (Ci-8 alkyI)paminocarbonylamino (Ci-8 alkyI)paminocarbonylamino 01-6 alkyl, (aryl)paminocarbonyiamino Cl-6 alkyl, (aryl Ci- alkyI)paminocarbonylamino, (aryl Ci-8 alkyl)paminocarbonylamino 01.6 alkyl, amninosulfonmylamnino 01.6 alkyl, (Ci- al kyl)paminosu Ifon ylamino, (0i-8 alkyl)paminosulfonylamino 01.6 alkyl, (aryl)paminosulfonylamino 01.6 alkyl, (aryl Cvs8 alkyl)paminosulfonylamino, j! (aryl Ois8 alkyl)paminosulfonylamino 01.6 alkyl, [R:\LIBAA]08974.doc:sak Ci-6 alkylsulfonyl, C1-6 alkylsulfonyl C1-6 alkyl, arylsulfonyl Ci-6 alkyl, aryl C1-6 alkylsulfonyl, aryl Ci-6 alkylsulfonyl C1.6 alkyl, C1-6 alkylcarbonyl, C1-6 alkylcarbonyl C1-6 alkyl, arylcarbonyl Ci.6 alkyl, aryl C1-6 alkylcarbonyl, 10 aryl C1-6 alkylcarbonyl C1-6 alkyl, C1-6 alkylthiocarbonylamino, Ci-6 alkylthiocarbonylamino C1-6 alkyl, arylthiocarbonylamino Ci-6 alkyl, aryl Ci-6 alkylthiocarbonylamino, aryl C1-6 alkylthiocarbonylamino C1-6 alkyl, alkyl)paminocarbonyl C1-6 alkyl, (aryl)paminocarbonyl C1-6 alkyl, (aryl C1i- alkyl)paminocarbonyl, and (aryl Ci-s alkyl)paminocarbonyl C1.6 alkyl; wherein any of the alkyl group of R 1 0

R'

1

R

12 and R 13 are either unsubstituted or substituted with one to three R 1 substituents; wherein each m is independently an integer from 0 to 6; each n is independently an integer from 0 to 6; each p is independently an integer from 0 to 2; each r is independently an integer from 1 to 3; each s is independently an integer from 0 to 3; each t is an integer from 0 to 3; and v is independently an integer from 0 to 6; and the pharmaceutically acceptable salts thereof.

The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention and a pharmaceutical acceptable carrier.

The present invention also relates to methods for making the pharmaceutical compositions of S the present invention.

[R:\LJBAA]08974.doc:sak 21 The present invention also relates to methods for eliciting an integrin receptor antagonising effect in a mammal in need thereof by administering the compounds and pharmaceutical compositions of the present invention.

The present invention also relates to methods for inhibiting bone resorption, restenosis, atherosclerosis, inflammation, viral disease, diabetic retinopathy, macular degeneration, angiogenesis, tumour growth, and metastasis by administering the compounds and pharmaceutical compositions of the present invention.

The present invention also relates to methods for treating osteoporosis by administering the compounds and pharmaceutical compositions of the present invention.

e

S**

*o* [R:\LIBAA]08974.doc:sak THI PAEI ETBAN NETOAL [R:\LIBAA]08974.doc:sak 23 a. a a a a a a a THIS PAGE IS LEFT BLANK INTENTIONALLY a a..

a a a a a. a a.

a.

[R:\LIBAA]08974.doc:sak Detailed Description of the Invention The present invention relates to compounds useful as integrin receptor antagonists.

Re~presentative compounds of the present invention are described by the following chemical formula: R6 W-X-Y R R 0R R 0R 5R8 wherein W is selected from the group consisting of i R1

R

1 RN R

RR

NC

NN~

NH and H X is 10 -(CH 2 wherein any methylene (CH 2 carbon atom is either unsubstituted or substituted ****with one or two R 1 substituents; Y is selected from the group consisting of (CH2)m-,

(CH

2 )m0O(CH 2

-(CH

2 )mNR 4 -(CH2),

-(CH

2 )mS(CH2)n-,

-(CH

2 )mSO-(CH2)n-,

-(CH

2 )mSO2-(CH2)n-,

-(CH

2 )m0O(CH 2 )n0O(CH2)p-,

-(CH

2 )mO(CH 2 )n-NR4-CH2)p-,

-(CH

2 )m-NR4-(CH 2 )n-NR 4

-(CH

2

-(CH

2 )m0O(CH2)n-S(CH2)p-,

-(CH

2 )mS(CH 2 )nS(CH2)p-,

-(CH

2 )mNR 4 (CH2)nS(CH2)p-,

-(CH

2 )mNR 4

(CH

2 )n0O(CH2)p-, R -(CH 2 )mS(CH 2 )n0O(CH2)p-, and

(CH

2 )mS(CH2)n-NR 4 -(CH2)p-, [R:\L1BAA]08974.dOC:sak wherein any methylene (OH 2 carbon atom in Y, other than in R 4 can be substituted by one or two

R

3 substituents; Z is 0 R10R10R0 Ny yNy 1_~ 0 0 0 101 ,and 0

R

1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, Ci-io alkyl, 03-8 cycloalkyl, 03-8 cycloheteroalkyl, 0348 cycloalkyl Oi-6 alkyl, 03-8 cycloheteroalkyl Ci-6 alkyl, aryl, aryl 01-8 alkyl, amino, amino 0148 alkyl, C1-3 acylamino, C1-3 acylamino C1-8 alkyl, (014 alkyl)pamino, (0146 alkyl)pamino 0148 alkyl, 0 0 0 0 C1- aikoxy, C1-4 alkoxy 01-6 alkyl, hydroxycarbonyl, hydroxycarbonyl 01-6 alkyl, 01.3 alkoxycarbonyl, C1-3 alkoxycarbonyl 0146 alkyl, hydroxycarbonyl- 0146 alkyloxy, hydroxy, hydroxy 0146 alkyl, 01-6 alkyloxy- 0146 alkyl, n itro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, 0148 alkyi-S(O)p, (0148 alkyi)paminocarbonyl, 0148 alkyloxycarbonylamino, (0148 alkyl)paminocarbonyloxy, (aryl 01-8 alkyl)pamino, (aryI)pamino, aryl 0148 alkylsulfonylamino, and 01-8 alkylsulfonylamino; or two R 1 substituents, when on the same carbon atom, are taken together with the carbon atom to which they are attached to form a carbonyl group; each R 3 is independently selected from the group consisting of hydrogen, aryl, -IAaryl-(H2),O-(CH2)s-, -v aryi-(CH2),S(O)p-(CH2)s-, [R:\LIBAA]08974.doc:sak aryI-(CH2)rC(O)-(CH2)s-, aryl-(CH2)rC(O)-N (R 4

)-(CH

2 aryl-(CH2),N(R 4 halogen, hydroxyl, oxo, trifluoromethyl, C1-8 alkylcarbonylamino, to1 aryl C1.5 alkoxy, 01-5 alkoxycarbonyl, (0148 alkyI)paminocarbonyI,

C

1 -6 aikylcarbonyloxy, C3-8 cycloalkyl, (Ci-6 alkyl)pamino, amino C 1 -6 alkyl, arylamninocarbonyl, aryl C1-5 aikylamninocarbonyl, amninocarbonyl, 20 amninocarbonyl Cl.6 alkyl, hydroxycarbonyl, hydroxycarbonyl 01.6 alkyl, 03.7 Cy-C-(aHky-C -C2r 01.6 alkyla-C=-C-(CH2)t-, HC3- (0H2)tky-CC(H)- CiarlkI-CCH-(C2

C

37 clylalyl-C=C-(H 2 aCH=CH-(H2)t-,

C

1 -6 alkyyl-CH=CH-(CH2)t-, C1-6 alkyl-S02-(CH2)t-, ~iRAL, C016 alkylaryl-S02-(CH2)t-, 01-6 alkoxy, [R:\LIBAA]08974.doc:sak aryl C,-6 alkoxy, aryl Ci-6 alkyl, (aryI)pamino, (aryI)pamino Ci.6 alkyl, (aryl Cl-6 alkyI)pamino, (aryl Ci-6 alkyl)pamino Ci-6 alkyl, arylcarbonyloxy, aryl Ci-6 alkylcarbonyloxy, 10 (Cl-6 alkyl)paminocarbonyloxy, :Ci-8 alkylsuylfonylamino, arylsulfonylamnino, C,-8 alkylsulfonylamnino Ci-6 alkyl, arylsulfonylamnino Ci-6 alkyl, aryl Cl-6 alkylsulfonylamnino, aryl CI-6 alkylsulfonylamnino Cl-6 alkyl, Cl- alkoxycarbonylamnino, S..Cl- alkoxycarbonylamnino C 14 8 alkyl, aryloxycarbonylamnino Ci-8 alkyl, 20 aryl Cl-8 alkoxycarbonylamnino, aryl C,-8 alkoxycarbonylamnino C,.8 alkyl, C,-8 alkylcarbonylamino, C,.8 alkylcarbonylamino C1.6 alkyl, arylcarbonylamino Ci-6 alkyl, aryl C,-6 alkylcarbonylamino, aryl C,-6 alkylcarbonylamino C,-6 alkyl, amninocarbonylamnino C,-6 alkyl, (Cl-8 alkyI)paminocarbonylamino, (Cl-8 alkyi)paminocarbonylamino C,-6 alkyl, (aryI)paminocarbonylamino Ci-6 alkyl, (aryl C,-8 alkyI)paminocarbonylamino, (aryl Cl-8 alkyl)paminocarbonylamino C 1 -6 alkyl, amninosulfonylamnino Cis6 alkyl,

(C

14 8 alkyl)paminosulfonylamino, 3 (Cl-8 alkyI)paminosu Ifonyl amino C,-6 alkyl, [R:\LIBAA]08974.doc:sak (aryl) pamninosulfonylamino C1-6 alkyl, (aryl Ci-8 alkyl) paminosulfonylamino, (aryl Ci-8 alkyl) pamninosulfonylamino C 16 alkyl, Ci-6 alkylsulfonyl, ~C1-6 alkylsulfonyl Ci.

6 alkyl, arylsulfonyl C,.

6 alkyl, aryl Ci-6 alkylsulfonyl, aryl C1-6 alkylsulfonyl 01-6 alkyl, Cis, alkylcarbonyl, :10 01.6 alkylcarbonyl Ci-6 alkyl, arylcarbonyl C 1 -6 alkyl, aryl C1-6 alkylcarbonyl, aryl Ci-6 alkylcarbonyl 01.6 alkyl, 01.6 alkylthiocarbonylamino, Ci-6 alkylthiocarbonylamino 01-6 alkyl, arylthiocarbonylamino C1-6 alkyl, 0 aryl 01.6 alkylthiocarbonylamino, aryl Ci-6 alkylthiocarbonylamino 01-6 alkyl, *ewe (01.6 alkyl)paminocarbonyl Ci-6 alkyl, 20 (aryI)paminocarbonyl 01-6 alkyl, *00 *06 9(aryl Oi-8 alkyl)paminocarbonyl, and (aryl C1-8 alkyl)paminocarbonyl 01-6 alkyl; or two R 3 substituents, when on the same carbon atom are taken together with the carbon atom to which they are attached to form a carbonyl group or a cyclopropyl group, wherein any of the alkyl groups of R 3 are either unsubstituted or substituted with one to three R 1 substituents, and provided that each R 3 is selected such that in the resultant compound the carbon atom or atoms to which R 3 is attached is itself attached to no more than one heteroatom; each R 4 is independently selected from the group consisting of hydrogen, aryl, aminocarbonyl, C3-8 cycloalkyl, amino 01.6 alkyl, (aryI)paminocarbonyl, 3 5 (aryl 01.5 alkyl)paminocarbonyl, LuJ [R:\LIBAA]08974.doc:sak hydroxycarbonyl C1-6 alkyl,

C

14 8 alkyl, aryl C1-6 alkyl, (Ci- 6 alkyl)pamino C 2 -6 alkyl, (aryl C1-6 alkyl)pamino C2-6 alkyl, Ci-8 alkylsulfonyl, Ci-8 alkoxycarbonyl, aryloxycarbonyl, aryl C 1 -8 alkoxycarbonyl,

C

1 -8 alkylcarbonyl, arylcarbonyl, aryl C1-6 alkylcarbonyl, (Cl-8 alkyl)paminocarbonyl, aminosulfonyl, Cl48 alkylaminosulfonyl, (aryl)paminosulfonyl, (aryl Ci-8 alkyl)paminosulfonyl, arylsulfonyl, 000.6 aryl C 1 -6 alkylsulfonyl, 20 C1-6 alkylthiocarbonyl, ::O~oaryithiocarbonyl, and 0 0 aryl Ci-6 alkylthiocarbonyl, wherein any of the alkyl groups of R 4 are either unsubstituted or substituted with one to three R 1 substituents;

R

5 and R 6 are each independently selected from the group consisting of hydrogen, Ci-io alkyl, aryl, aryl-(CH2)rO-(CH2),-, aryl-(CH2),S(O)p-(CH2)s-, aryl-(CH2),C(O)-(CH2)s-, aryl-(CH2)rC(O)-N (R 4

)-(CH

2 aryl-(CH2) 1

-N(R

4 C-?AI rl(H2,(4-'H)halogen, uLJ kNT 0' [R:\LIBAA]08974.doc:sak hydroxyl, 0148 alkylcarbonylamino, aryl 01-5 alkoxy, 01-5 alkoxycarbonyl, (0148 alkyl)paminocarbonyl, 0146 alkylcarbonyloxy, 03-8 cycloalkyl,

(C

14 6 alkyI)pamino, amino 0146 alkyl, 10 arylamninocarbonyl, aryl Cl- alkylamninocarbonyl, 4. 0: aminocarbonyl, amninocarbonyl 0146 alkyl, o. hydroxycarbonyl, hydroxycarbonyl Cis6 alkyl, .o~oo: C014 alky-C0=0-(0H2)t-, 03.7 cycloalkyI-C=-C-(CH2)t-, .0 :20 0 1 -6 a lky lary-C CH 2) :oo CH 2 =CH-(0H 2 014i- alkyl-CH=CH-(CH2)r-, 03.7 cycloalkyl-CH=CH-(0H2)t-, aryl-CH=CH-(0H2)t-, 0146 alkylaryl-CH=CH-(CH2)t-, 0146 alkyl-S02-(CH2)t-, 0146 alkylaryl-S02-(CH2)t-, 0146 alkoxy, aryl 01-6 alkoxy, aryl 0146 alkyl, (0146 aikyl)pamino 0146 alkyl, (aryI)pamino, (aryI)pamino 0146 alkyl, Tl (aryl 01-6 alkyl)pamino, ,z 35 (aryl 0146 alkyI)pamino 0146 alkyl, [R:\LIBAA]08974.doc:sak arylcarbonyloxy, aryl C146 alkyicarbonyloxy, (Ci-6 alkyI)paminocarbonyloxy,

C

1 -8 alkylsuylfonylamino, arylsulfonylamnino,

C

1 -8 alkylsulfonylamnino Cl-6 alkyl, arylsulfonylamnino C1-6 alkyl, aryl Cl-6 alkylsulfonylamino, aryl Cl-6 alkylsulfonylamnino C1-6 alkyl, :10 C 1 -8 alkoxycarbonylamino, Ci-8 alkoxycarbonylamnino C 1 -8 alkyl, arylxycarbonylamino C 1 -8 alkyl, aryl 0148 alkoxycarbonylamino, aryl 0148 alkoxycarbonylamnino 0148 alkyl,

C

14 B alkylcarbonyl amino, 0148 alkylcarbonylamino C1-6 alkyl, arylarbonylamino C 14 6 alkyl, aryl Cl-6 alkylcarbonylamino, aryl Cl-6 alkylcarbonylamino Cl-6 alkyl, amninocarbonylamnino Ci46 alkyl, (Cl- 4 alkyl)paminocarbonylamino, (014 alkyl)paminocarbonylamino Ci-6 alkyl, (aryI)paminocarbonylamino Ci-6 alkyl, (aryl C148 aikyI)paminocarbonylamino, (aryl Cl48 alkyl)paminocarbonylamino 0146 alkyl, amninosulfonmylamnino Ci.6 alkyl, (0148 alkyl)paminosulfonylamino,

(C

14 8 alkyI)paminosulfonylamino Cl-6 alkyl, (aryl)paminosulfonylamnino C 14 6 aikyl, (aryl C 1 4 8 alkyI)paminosulfonylamino, (aryl C1-8 alkyl) pamninosulfonylamnino 0146 alkyl, 0146 alkylsulfonyl, n ?,AL 01 alkylsulfonyl Cl-6 alkyl, -jD arylsulfonyl 0146 alkyl, r3 aryl Ci- 6 alkylsulfoiiyI, [R:\LIBAA]08974.doc:sak aryl C,-6 alkylsulfonyl C 1 -6 alkyl, Ci-6 alkylcarbonyl, Ci-6 alkylcarbonyl Ci-6 alkyl,.

arylcarbonyl Ci-6 alkyl, ~aryl Cv-6 alkylcarbonyl, aryl C1-6 alkylcarbonyl C1-6 alkyl, C1-6 alkylthiocarbonylamino, Ci-6 alkylthiocarbonylamino Ci- alkyl, arylthiocarbonylamino C 16 alkyl, aryl C1-6alkylthiocarbonylamino, aryl Ci-6 alkylthiocarbonylamino C1-6 alkyl,

(C

14 8 alkyl)paminocarbonyl C 1 -6 alkyl, (aryI)paminocarbonyI C1-6 alkyl, (aryl C 14 8 alkyl)paminocarbonyl, and (aryl C 14 8 alkyl)paminocarbonyl Ci.

6 alkyl; or R 5 and R 6 are taken together with the carbon atom to which they are attached to form a carbonyl group, wherein any of the alkyl groups of R 5 and R 6 are either unsubstituted or substituted with one to three R 1 substituents, and provided that each R 5 and R 6 are selected such that in the resultant compound the carbon atom to which R 5 and R 6 are attached is itself attached to no more than one heteroatom;

R

7 and R 8 are each independently selected from the group consisting of hydrogen, C1.iao alkyl, aryl, aryl-(CH2)1O-(CH2)S-, aryl-(CH 2 )rS(O)p-(CH2)s-, aryl-(CH2)r-C(O)-(CH2)s-, aryl-(CH2)rC(O)-N (R 4

)-(CH

2 aryl-(CH2)r-N(R 4 aryl-(CH2)-N (R 4 halogen, hydroxyl, Ci-8 alkylcarbonylamino, aryl C 15 alkoxy, [R:\LIBAA]08974doc:sak C1.

5 alkoxycarbonyl, (Ol alkyI)paminocarbonyl, 01.6 alkyicarbonyloxy, C3-8 cycloalkyl, (Cl-6 alkyI)pamino, amino 01-6 alkyl, arylaminocarbonyl, aryl 01.5 alkylamninocarbonyl, amninocarbonyl, amninocarbonyl C1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl 01-6 alkyl, 03.7 ~~Cy-C-oaHky-0 -CH)- 01.6 alkylary-C0-(H2), 0H2=CH-(CH2)t-, 01.6 alkyl-CH=CH-(CH2)t-, 20C7 cycloalkyl-CH=CH-(0H2)t-, aryl-CH=OH-(CH2)t-, 01.6 alkylaryl-CH=OH-(CH2)t-, 01.6 alkyl-S02-(CH2)t-, 01.6 alkylaryl-S02-(CH2)t-, 01.6 alkoxy, aryl 01.6 alkoxy, aryl 01.6 alkyl, (01.6 alkyl)pamino 01.6 alkyl, (ary)pamino, (aryl)pamino 01-6 alkyl, (aryl 01.6 alkyI)pamino, (aryl 01.6 alkyI)pamino 01.6 alkyl, Cr A Larylcarbonyloxy, aryl C1-6 alkylcarbonyloxy, p'ij (01.6 alkyl)paminocarbonyloxy, [R:\LIBAA]08974.doc:sak C1-8 alkylsuylfonylamino, arylcarbonylamino, arylsuif on yla min 0, 01-8 alkylsulfonylamino Cl-6 alkyl, arylsulfonylamino Cl-6 alkyl, aryl C016 alkylsulfonylamnino, aryl 0146 alkylsulfonylamino C016 alkyl, C0-8 alkoxycarbonylamnino, 01-8 alkoxycarbonylamnino 01-8 alkyl, aryloxycarbonylamino 01-8 alkyl, aryl 01.8 alkoxycarbonylamino, aryl C1-8 alkoxycarbonylamino C1-8 alkyl,

C,-

8 alkylcarbonylamino, SC,-8 alkylcarbonyl amino 01-6 alkyl, arylcarbonylamino C1.

6 alkyl, aryl C1-6 aikylcarbonylamino, aryl 01-6 alkylcarbonyiamino 01-6 alkyl, aminocarbonylamnino C 1 -6 alkyl, arylamninocarbonylamnino, (Cl-a alkyl)paminocarbonylamino, (0148 alkyI)paminocarbonyiamino Ci-6 alkyl, (aryI)paminocarbonylamino C 1 -6 alkyl, (aryl 01.8 alkyl)paminocarbonylamino, (aryi C1.8 alkyI)paminocarbonylamino C 1 -6 alkyl, aminosulfonmylamnino 01.8 alkyl, (Cl- 4 alkyI)paminosulfonylamino, (Ci..a alkyt)paminosulfonylamino C1.6 alkyl, (aryI)paminosulfonylamino 0146 alkyl, (aryl 01-8 alkyI)paminosulfonylamino, (aryl C1-8 alkyl) paminosulfonylamino Ci-6 alkyl, 01.8 alkylsulfonyl, 01.8 alkylsulfonyl C1-6 alkyl, arysulfonyl 01.8 alkyl, aryl 01-6 alkylsulfonyl, rL aryl 01-6 alkyisulfonyl C 14 6 alkyl, [R:\LIBAA]08974.doc:sak Ci-6 alkylcarbonyl, C1-6 alkylcarbonyl C1- 6 alkyl, arylcarbonyl C1-6 alkyl, aryl C 1 -6 alkylcarbonyl, aryl C1-6 alkylcarbonyl Ci-6 alkyl, C1-6 alkylthiocarbonylamino, CI-6 alkylthiocarbonylamino C1-6 alkyl, arylthiocarbonylamino Cis6 alkyl, aryl Ci-6 alkylthiocarbonylamino, aryl Cvs6 alkylthiocarbonylamino C1-6 alkyl, (Ci-8 alkyl)paminocarbonyl C1-6 alkyl, (aryI)paminocarbonyl Ci-6 alkyl, (aryl C 1 -8 alkyl)paminocarbonyl, (aryl Ci-8 alkyI)paminocarbonyl Ci-6 alkyl, and

C

72 0 polycyclyl Co-8 alkylsulfonylamino; wherein any of the alkyl groups of R 7 and R 8 are either unsubstituted or substituted with one to three RI substituents, and provided that each R 7 and R 8 are selected such that in the resultant compound the carbon atom to which R 7 and R 8 are attached is itself attached to no more than one 20 heteroatom;

R

9 is selected from the group consisting of hydrogen,

C

1 -8 alkyl, aryl, aryl C 1 -8 alkyl, Ci-8 alkylcarbonyloxy C,4 alkyl, aryl Ci-8 alkylcarbonyloxy C14 alkyl,

C

1 -8 alkylaminocarbonylmethylene, and C1-8 dialkylaminocarbonylmethylene; RIO, R 1 1

R

1 2 and R 13 are each independently selected from the group consisting of hydrogen,

C

1 -8 alkyl, aryl, halogen, hydroxyl, k'~oxo, [R:\LIBAA]08974.doc:sak amninocarbonyl, C3-8 cycloalkyl, amino Cl-6 alkyl, (aryI)paminocarbonyI, hydroxycarbonyt, (aryl C 15 alkyI)paminocarbonyI, hydroxycarbonyl C,-6 alkyl, aryl C1. alkyl, (Ci-6 alkyl)pamino C 1 -6 alkyl, (aryl C,-6 alkyI)pamino C 2 .6 alkyl, Cl- alkylsulfonyl, Cl-8 alkoxycarbonyl, ar*oyaronl aryl C- loxycarbonyl, ar C1 alkycarbonyl, Cvalkaboylabo, aryl C- lycarbonyl, arCi alkylmcarbonyl, akyI)ainocarony, (ar aminosulfonyl, C ,8 alkylpaminosulfonyl, (arya sufony, (~~~arylsC 18 anyI)ainsfnI arC1- alkylsulfonyl, arylsuI lfoylabnl arlCv alkylsulfaronyl, arylti ycarbonyl, arC 1 6 alkythiocarbonyl, aryl-(CH2)r-O-(CH2)s-, aryl-(CH 2 )rS(O)p-(CH 2 aryl-(CH 2 )rC(O)-(CH2)s-,

LUI

3 5 CY aryI-(CH2)rN(R 4 [R:\LIBAA]08974.doc:sak 03HCy-C-oiyCCH)-(C2) s C 14 alkyla-C=-C-(CH2)t-, CC-(lakCH)r, H)t

C

14 alk-CHCH-(C 2 Clo6alkyl-C=C-(CH 2 aCH=CH-(CH2)t-, 014- aikyla-CH=CH-(H2)t-, 0146 alkylaryl-S02-(CH2)t-, Ci-8 aikylcarbonylamino, aryl Cli5 alkoxy, 01.5 alkoxycarbonyl, (0148 aikyl)paminocarbonyl, Cl-6 alkylcarbonyloxy, aly.*mio aminocarbonyl Cl-6 alkyl, 0146 alkoxy, :~'aryl C1-6 alkoxy, (aryl)pamino, (aryI)pamino C1.6 alkyl, (aryl 0146 alkyl)pamino, (aryl 0146 alkyl)pamino 0146 alkyl, arycarbonyloxy, aryl 0146 alkylcarbonyloxy, (01-6 alkyl)paminocarbonyloxy, 0148 alkylsulfonylamino, aryisulfonylamino, Ci-8 alkylsulfonylamino Ci- alkyl, arylsulfonylamino Cl-6 alkyl, aryl 01-6 alkylsulfonylamino, ID, A aryl 01-6 alkylsulfonylamino C 1 alkyl, Ci-8 alkoxycarbonylamino, [R:\LIBAA]08974.doc:sak

C

1 -8 alkoxycarbonylamino Cl- 4 alkyl, aryloxycarbonylamnino C 1 4 8 alkyl, aryl Cl-8 alkoxycarbonylamino, aryl C 1 -8 alkoxycarbonylamino Ci-8 alkyl, Cl-8 alkylcarbonylamino, Cl48 alkylcarbonylamino Ci.6alkyl, arylcarbonylamino Ci-6 alkyl, aryl Ci-6 alkylcarbonylamino, aryl Ci.6 alkylcarbonylamino Cl-6 alkyl, amninocarbonylamnino Cl46 alkyl,

(C

1 4 alkyI)paminocarbonylamino (Ci-8 alkyl)paminocarbonylamino Ci-6 alkyl, (aryl)paminocarbonylamino C 1 46 alkyl, (aryl C148 alkyl)paminocarbonylamino, (aryl Ci-8 alkyI)paminocarbonylamino C 1 -6 alkyl, aminosulfonmylamino C 1 .6 alkyl, (Ci-8 alkyI)paminosuifonylamino, (Cl- 8 aikyl)paminosulfonylamino C,-6 alkyl, ****(aryl)paminosulfonylamino C 1 -6 alkyl, (aryl C 14 8 alkyI)paminosulfonylamino, (aryl 0148 alkyI)paminosulfonylamino 0146 alkyl,

C

1 4 alkylsuifonyl, C1., alkylsulfonyl 01.6 alkyl, arylsulfonyl 01. alkyl, aryl C1.6 alkylsulfonyl, ary l 16 alkylsulfonyl Cl-6 alkyl, 01.6 alkylcarbonyl,

C

14 6 alkylcarbonyl Ci-6 alkyl, arylcarbonyl Cl-6 alkyl, aryl Cl-6 alkylcarbonyl, aryl Ci-6 alkylcarbonyl C 1 4 6 alkyl, Cl-6 alkylth iocarbonyl amino, r RA Ci-6 alkylthiocarbonylamnino 01.6 alkyl, arylthiocarbonylamnino 01.6 alkyl, aryl Ci-6 alkyithiocarbonylamnino, [R:\LIBAA]08974.doc:sak aryl Ci- alkylthiocarbonylamino C16 alkyl, (Ci- alkyl)paminocarbonyl Ci-6 alkyl, (aryl)paminocarbonyl C1s alkyl, (aryl Ci- alkyl)paminocarbonyl, and (aryl C 1 alkyl)paminocarbonyl Ci- alkyl; wherein any of the alkyl group of R 0

R

1 1

R

1 2 and R 13 are either unsubstituted or substituted with one to three R 1 substituents; wherein each m is independently an integer from 0 to 6; each n is independently an integer from 0 to 6; each p is independently an integer from 0 to 2; S'each r is independently an integer from 1 to 3; each s is independently an integer from 0 to 3; each t is an integer from 0 to 3; and v is independently an integer from 0 to 6; and the pharmaceutically acceptable salts thereof.

S" In the compounds of the present invention, W is preferably a 6-membered monocyclic aromatic or nonaromatic ring system having 1 or 2 nitrogen atoms wherein each carbon atom is either unsubstituted or substituted with one R 1 substituent, or 0 [R:\LIBAA]08974.doc:sak WO 99/30713 PCT/US98/26485 a 9- to 14-membered polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring system has 0, 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, 0, and S wherein the ring nitrogen atoms are unsubstituted or substituted with one R 1 substituent and the ring carbon atoms are unsubstituted or substituted with one or two R 1 substituents.

More preferably, W is selected from the group consisting of R' R' N N NN H

H

N I F1N4

R

1 {z

R

1

H

H

and Most preferably W is

R

1

R

1 or N N Y N N ss

H

In the compounds of the present invention, X is preferably wherein any methylene (CH2) carbon atom is either unsubstituted or substituted with one or two R1 substituents.

More preferably X is a direct bond, that is, v is 0.

In the compounds of the present invention, Y is preferably selected from the group consisting of -(CH2)m-, WO 99/30713 WO 99/07 13PCTIUS98/26485 -(CH2)m-O-(CH2)n-, -(GCH2)m-NR 4 -(CH2)n-, -(CH2)m-S-(CH2)n-, -(GH2)m-S0-(CH2)n-, -(CH2)m-S02-(CH2)n-, -(CH2)m-O-(CH2)n-O-(CH2)p-, -(CH2)m-O-(CH2)n-NR 4 -(CH2)p-, -(CH2)m-NR 4 -(CH2)n-N7R 4 and -(CH2)m-NR 4 -(CH2)n-O-(CH2)p-, wherein any methylene (CH2) carbon atom in Y, other than in R 4 can be substituted by one or two R 3 substituents.

More preferably Y is selected from the group consisting of (CH2)m, (CH2)m-S-(CH2)n, and (CH2)m-NR 4 -(GH2)n, wherein any methylene (CH2) carbon atom in Y, other than in R 4 can be substituted by one or two R 3 substituents.

In the compounds of the present invention, Z is preferably selected from the group consisting of N N 201 N -41- WO 99/30713 WO 9930713PCT/1US98/26485

NJ

0

HN

0 and -N- More preferably Z is selected from the group consisting of 1 1 an \NyN~l 0 -42- WO 99/30713 PCT/US98/26485 Most preferably Z is Ri 1

R

10 N NI-- .or In the compounds of the present invention, R1 and R 2 are preferably selected from the group consisting of hydrogen, halogen, Clalkyl, C3-8 cycloalkyl, C3-8 cycloheteroalkyl, hydroxy, nitro, cyano, trifluoromethyl, and trifluoromethoxy.

More preferably, R1 and R2 are selected from the group consisting of hydrogen, halogen, C1-10 alkyl, C3-8 cycloalkyl, trifluoromethyl, and trifluoromethoxy.

In the compounds of the present invention, R 3 is preferably selected from the group consisting of hydrogen, fluoro, trifluoromethyl, aryl, C1-8 alkyl, arylC1-6 alkyl hydroxyl, oxo, arylaminocarbonyl, aryl C1-5 alkylaminocarbonyl, aminocarbonyl, and aminocarbonyl C1-6 alkyl.

More preferably, R 3 is selected from the group consisting of fluoro, aryl, C1-8 alkyl, -43- WO 99/30713 WO 9930713PCTIUS98/26485 arylCl..6 alkyl hydroxyl, oxo, and arylaminocarbonyl.

In the compounds of the present invention, R 4 is preferably selected from the group consisting of hydrogen, aryl, C3-8 cycloalkyl, C1-.8 alkyl, C1-8 alkylcarbonyl, arylcarbonyl, C1-.6 alkylsulfonyl, arylsulfonyl, arylCl...alkylsulfonyl, aryiC 1..alkylcarbonyl, C l-8alkylaminocarbonyl, aryiC arylCl...alkoxycarbonyl, and C l-8alkoxycarbonyl.

More preferably, R 4 is selected from the group consisting of hydrogen, C1-.8 alkyl, C1-8 alkylcarbonyl, arylcarbonyl, arylC I..alkylcarbonyl, C1-6 alkylsulfonyl, arylsulfonyl, and aryiC l...alkylsulfonyl.

In one embodiment of the present invention, R 5 and R 6 are each independently selected from the group consisting of hydrogen, -44- WO 99/30713 PCT/US98/26485 aryl, C1-8 alkyl, aryl-C=C-(CH2)t-, aryl C1-6 alkyl, CH2=CH-(CH2)t-, and HC-C-(CH2)t-.

In a class of this embodiment of the present invention, R 6 is hydrogen and R 5 is selected from the group consisting of hydrogen, aryl, C1-8 alkyl, aryl-C-C-(CH2)t-, aryl C1-6 alkyl, CH2=CH-(CH2)t-, and HC-C-(CH2)t-.

In a subclass of this class of the present invention, R 6

R

7 and R 8 are each hydrogen and R 5 is selected from the group consisting of hydrogen, aryl, C1-8 alkyl, aryl-C=C-(CH2)t-, aryl C1-6 alkyl, CH2=CH-(CH2)t-, and HC=C-(CH2)t-.

In another embodiment of the present invention, R 7 and R 8 are each independently selected from the group consisting of hydrogen, aryl, C1-8 alkylcarbonylamino, arylcarbonylamino, C1-8 alkylsulfonylamino, arylsulfonylamino, WO 99/30713 PTU9/68 PCTIUS98/26485 C1-8 alkylsulfonylamino C1l6 alkyl, arylsulfonylamino C 1-6 alkyl, aryl. C1..6 alkylsulfonylarnino, aryl. C1-6 alkylsulfonylamino C1.6 alkyl, C1-8 alkoxycarbonylainino, C01-8 alkoxycarbonylamino Ci.1-8 alkyl, aryloxycarbonylamino C1..8 alkyl, aryl C1..8 alkoxycarbonylamino, aryl C1-8 alkoxycarbonylainino C1-8 alkyl, C1-8 alkylcarbonylamino C1-6 alkyl, arylcarbonylainino C1-6 alkyl, aryl C1..6 alkylcarbonylamino, aryl Cl-6 alkylcarbonylamino C1.-6 alkyl, aminocarbonylamino C1-6 alkyl, (C1.8 alkyl)paminocarbonylamino, (C 1-8 alkyl)patninocarbonylamino C1..6 alkyl, (aryl)paminocarbonylamino C 1-6 alkyl, (aryl C1-8 alkyl)paminocarbonylamino, (aryl C1..8 alkyl)paniinocarbonylainino 01-6 alkyl, aminosulfonylamino C1-6 alkyl, (C 1-8 alkyl)paminosulfonylamino, (C 1-8 alkyl)paminosulfonylamino C1-6 alkyl, (aryl)paminosulfonylamino C1-6 alkyl, (aryl C1..8 alkyl)paminosulfonylamino, (aryl C1-8 alkyl)paininosulfonylainino C1.-6 alkyl, 01-6 alkyithiocarbonylamino, C1-.6 alkylthiocarbonylamino C1-6 alkyl, aryitbiocarbonylamino C1-6 alkyl, aryl C1..6 alkylthiocarbonylamino, and aryl 01-6 alkylthiocarbonylamino C1-6 alkyl.

In a class of this embodiment of the present invention, R 8 is hydrogen and R 7 is selected from the group consisting of consisting of hydrogen, -46- WO 99/30713 WO 9930713PCTIUS598/2 6485 aryl, C1-8 alkylcarbonylamino, aryl C1-6 alkylcarbonylainino, arylcarbonylamino, C1-8 alkylsulfonylamino, aryl C1-6 alkylsulfonylamino, arylsulfonylamino, C1-8 alkoxycarbonylamino, aryl C1-8 alkoxycarbonylainino, arylaminocarbonylamino, (C 1-8 alkyl)paminocarbonylamino, (aryl C1-8 alkyl)paminocarbonylamino, (C1-8 alkyl)paminosulfonylaniino, and (aryl C1-8 alkyl)paminosuflfonylamino.

In a subclass of this class of the present invention, R 5

R

6 and R 8 are each hydrogen and R 7 is selected from the group consisting of hydrogen, aryl, C1-8 alkylcarbonylamino, aryl C1-6 alkylcarbonylamino, arylcarbonylamino, 01-8 alkylsulfonylamino, aryl C1-6 alkylsulfonylamnino, arylsulfonylamino, 01-8 alkoxycarbonylaino, aryl C1-8 alkoxycarbonylamino, arylainino carbonylamino, (C 1-8 alkyl)paminocarbonylamino, (aryl C1-8 alkyl)paminocarbonylamino, (01-8 alkyl)paminosulfonylamino, and (aryl 01-8 alkyl)paminosulfonylamino& -47 WO 99/30713 PCT/US98/26485 In the compounds of the present invention, R 9 is preferably selected from the group consisting of hydrogen, methyl, and ethyl.

More preferably, R 9 is hydrogen.

In the compounds of the present invention, R 1 0

R

1 1

R

1 2 and R 1 3 are preferably each independently selected from the group consisting of hydrogen and C1-8 alkyl.

More preferably R 1 0

R

1 1

R

1 2 and R 1 3 are hydrogen.

In the compounds of the present invention, m is preferably an integer from 0 to 4, more preferably from 0 to 3.

In the compounds of the present invention, n is preferably an integer from 0 to 4, more preferably from 0 to 3.

In the compounds of the present invention, r is preferably an integer from 1 to 2.

In the compounds of the present invention, s is preferably an integer from 0 to 2.

In the compounds of the present invention, t is preferably an integer from 0 to 2, more preferably from 0 to 1.

In the compounds of the present invention, v is preferably 0.

In certain embodiments of the present invention the compounds have the formula with the following designated stereochemistry: R R R WXYZ K 00 2

R

9

R

7

R

8 wherein the substituents W, X, Y, Z, R 1

R

2

R

3

R

4

R

5

R

6

R

7

R

8

R

9

R

1 0

R

1 1

R

1 2 and R 1 3 and the subscripts m, n, p, r, s, t, and v are as described above.

Illustrative but nonlimiting examples of compounds of the present invention that are useful as integrin receptor antagonists are the following: -48- WO 99/30713 WO 9930713PCTIUS98/26485 ethyl 3(S)-(2,3-dihydro-benzofuran-6-yl)-3-{2-oxo-3-[3-(5,6,7,8-tetrahydro- 8]naphthyridin-2-yl)-propyl] -tetrahydro-pyriinidin- l-yl}-propionate; ethyl 3(S)-(3-fluorophenyl)-3-(2-oxo-3(S or ,6,7,8-tetrahydro- 8naphthyridin- 2-yl)-propyl]-piperi din- 1-yl)-propionate; ethyl 3(S)-(3-fluorophenyl)-3-(2-oxo-3(R or ,6,7,8-tetrahydro- 8]naphthyridin- 2-yl)-propyl]-piperidin- 1-yl)-propionate; 3(S)-(2,3-dihydro-benzofuran-6-yl)-3- (2-oxo-3-[3-(5,6,7,8-tetrahydro- [1,8]naphthyridin-2-yl)-propyl] -tetraliydro-pyrimidin- l-yl} -propi onic acid; 3(S)-(3-fluorophenyl)-3-(2-oxo-3(S or R)-[3-(5,6,7,8-tetrahydro- [1,8]naphthyridin-2-yl)-propyl]-piperidin- 1-yl)-propionic acid; 3(S)-(3-fluorophenyl)-3-(2-oxo-3(R or ,6,7 ,8-tetrahydro- [1,8]naphthyridin-2-yl)-propyl]-piperidin- 1-yl)-propionic acid; and the pharmaceutically acceptable salts thereof.

Further illustrative of the present invention are the compounds selected from the group consisting of: 3(S)-(2,3-dihydro-benzofuran-6-yl)-3- (2-oxo-3-[3-(5 ,6,7,8-tetrahydro- I 1,8]naphthyridin-2-yl)-propylll-tetrahydro-pyrimidin- l-yl} -propionic acid; 3(S)-(3-fluorophenyl)-3-(2-oxo-3(S or R)-[3-(5,6,7,8-tetrahydro- [1,8]naphthyridin-2 -yl)-propyl]-piperidin- 1-yl)-propionic acid; 3(S)-(3-fluorophenyl)-3-(2-oxo-3(R or S)4[3-(5,6,7,8-tetrahydro- 1,8]Inaphthyridin- 2-yl)- propyl] -pipe ri din- 1 propionic acid; and the pharmaceutically acceptable salts thereof.

-49- WO 99/30713 PCT/US98/26485 For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts." Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts.

Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.

Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, sodium or potassium salts; alkaline earth metal salts, calcium or magnesium salts; and salts formed with suitable organic ligands, quaternary ammonium salts.

The compounds of the present invention can have chiral centers and occur as racemates, racemic mixtures, diastereomeric mixtures, and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention. Therefore, where a compound is chiral, the separate enantiomers or diastereomers, substantially free of the other, are included within the scope of the invention; further included are all mixtures of the two enantiomers. Also included within the scope of the invention are polymorphs and hydrates of the compounds of the instant invention.

The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be WO 99/30713 PCT/US98/26485 functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985, which is incorporated by reference herein in its entirety. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu.

Thli term "therapeutically effective amount" shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician.

The term "integrin receptor antagonist," as used herein, refers to a compound which binds to and antagonizes either the av3 receptor, the avP5 receptor, or the avp6 receptor, or a compound which binds to and antagonizes combinations of these receptors (for example, a dual avp3/av35 receptor antagonist).

The term "bone resorption," as used herein, refers to the process by which osteoclasts degrade bone.

The term "alkyl" shall mean straight or branched chain alkanes of one to ten total carbon atoms, or any number within this range methyl, ethyl, 1-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.).

The term "alkenyl" shall mean straight or branched chain alkenes of two to ten total carbon atoms, or any number within this range.

The term "alkynyl" shall mean straight or branched chain alkynes of two to ten total carbon atoms, or any number within this range.

-51- WO 99/30713 WO 9930713PCTIUS98/26485 The term "cycloalkyl" shall mean cyclic rings of alkanes of three to eight total carbon atoms, or any number within this range cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).

The term "cycloheteroalkyl,' as used herein, shall mean a 3- to 8-membered fully saturated heterocyclic ring containing one or two heteroatoms chosen from N, 0 or S. Examples of cycloheteroalkyl groups include, but are not limited to piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, piperazinyl.

The term "alkoxy," as used herein, refers to straight or branched chain alkoxides of the number of carbon atoms specified alkoxy), or any number within this range methoxy, ethoxy, etc.).

Thd term "aryl," as used herein, refers to a monocyclic or polycycic system comprising at least one aromatic ring, wherein the monocylic or polycyclic system contains 0, 1, 2, 3, or 4 heteroatoms chosen from N, 0, or S, and wherein the monocylic or polycylic system is either unsubstituted or substituted with one or more groups independently selected from hydrogen, halogen, C 1-10 alkyl, C3-8 cYcloalkyl, aryl, arYl C1-8 alkyl, amino, amino C1-8 alkyl, 01-3 acylamino, C1..3 acylaniino C1-8 alkyl, C1-6 alkylamino, C1-6 alkylamino C1-8 alkyl, C1..6 dialkylarnino, C1..6 dialkylamino-C1..8 alkyl, C1-4 alkoxy, C1-4 alkoxy C1-.6 alkyl, hydroxycarbonyl, hydroxycarbonyl C1-6 alkyl, Ci..

alkoxycarbonyl, C1-3 alkoxycarbonyl C1-6 alkyl, hydroxycarbonyl C1-6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, cyano, trifluoromethyl, oxo or Ci..

5 alkylcarbonyloxy. Examples of aryl include, but are not limited to, phenyl, naphthyl, pyridyl, pyrazinyl, pyrimidinyl, imidazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, indolyl, thienyl, furyl, pyrryl, pyrazolyl, dihydrobenzofuryl, benzo(1,3) dioxolane, oxazolyl, isoxazolyl and thiazolyl, which are either unsubstituted or substituted' with one or more groups independently selected from hydrogen, halogen, 01-10 alkyl, C3-8 cycloalkyl, aryl, aryl C1..8 alkyl, amino, amino C1-8 alkyl, 01-3 acylamino, C1-3 acylamino C1-8 alkyl, C1-6 alkylamino, C1-6 alkyl amino-C1..8 alkyl, C1..6 dialkylainino, C1-6 dialkylamino C1-8 alkyl, C1-4 alkoxy, C1-4 alkoxy Cl..6 alkyl, hydroxycarbonyl, hydroxycarbonyl 01-6 alkyl, Ci-5 alkoxycarbonyl, C1-3 alkoxycarbonyl 52- WO 99/30713 PCT/US98/26485 C1-6 alkyl, hydroxycarbonyl C1-6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, cyano, trifluoromethyl, oxo or C1-5 alkylcarbonyloxy. Preferably, the aryl group is unsubstituted, mono-, di-, tri- or tetra-substituted with one to four of the above-named substituents; more preferably, the aryl group is unsubstituted, mono-., di- or tri-substituted with one to three of the above-named substituents; most preferably, the aryl group is unsubstituted, mono- or di-substituted with one to two of the abovenamed substituents.

Whenever the term "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent aryl CO-8 alkyl) it shall be interpreted as including those limitations given above for "alkyl" and "aryl." Designated numbers of carbon atoms C1-10) shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.

The terms "arylalkyl" and "alkylaryl" include an alkyl portion where alkyl is as defined above and to include an aryl portion where aryl is as defined above. Examples of arylalkyl include, but are not limited to, benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl, fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl, and thienylpropyl. Examples of alkylaryl include, but are not limited to, toluene, ethylbenzene, propylbenzene, methylpyridine, ethylpyridine, propylpyridine and butylpyridine.

In the compounds of the present invention, two R 1 substituents, when on the same carbon atom, can be taken together with the carbon to which they are attached to form a carbonyl group.

In the compounds of the present invention, two R 3 substituents, when on the same carbon atom, can be taken together with the carbon atom to which they are attached to form a carbonyl group. In such instances, the limitation, that in the resultant compound the carbon atom or atoms to which R 3 is attached is itself attached to no more than one heteroatom, does not apply. Also, in the compounds of the present invention, two R 3 substituents, when on the same carbon -53- WO 99/30713 PCT/US98/26485 atom, can be taken together with the carbon atom to which they are attached to form a cyclopropyl group.

In the compounds of the present invention, R 5 and R 6 can be taken together with the carbon atom to which they are attached to form a carbonyl group. In such instances, the limitation, that in the resultant compound the carbon atom to which R 5 and R 6 is attached is itself attached to no more than one heteroatom, does not apply.

The term "halogen" shall include iodine, bromine, chlorine, and fluorine.

The term "oxy" means an oxygen atom. The term "thio" means a sulfur atom. The term "oxo" means The term "carbonyl" means Th4 term "substituted" shall be deemed to include multiple degrees of substitution by a named substitutent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.

Under standard nonmenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. For example, a C1-5 alkylcarbonylamino C1-6 alkyl substituent is equivalent to

O

I I -C1- 6 alkyl-NH-C-C 1 5 alkyl.

In choosing compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e.

W, X, Y, Z, R 1

R

2

R

3

R

4

R

5

R

6

R

7

R

8

R

9

R

1 0 Rll, R 1 2 and R 1 3 and the subscripts m, n, p, r, s, t, and v are to be chosen in conformity with well-known principles of chemical structure connectivity.

Representative compounds of the present invention typically display submicromolar affinity for the integrin receptors, particularly -54- WO 99/30713 PCTIUS98/26485 the avp3, avp5, and/or cav36 receptors. Compounds of this invention are therefore useful for treating mammals suffering from a bone condition caused or mediated by increased bone resorption, who are in need of such therapy. Pharmacologically effective amounts of the compounds, including pharamaceutically acceptable salts thereof, are administered to the mammal, to inhibit the activity of mammalian osteoclasts.

The compounds of the present invention are administered in dosages effective to antagonize the av33 receptor where such treatment is needed, as, for example, in the prevention or treatment of osteoporosis.

Further exemplifying the invention is the method wherein the integrin receptor antagonizing effect is an avp3 antagonizing effect.

An illustration of the invention is the method wherein the avP3 antagonizing effect is selected from inhibition of bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, viral disease, tumor growth, or metastasis. Preferably, the av3 antagonizing effect is the inhibition of bone resorption.

An example of the invention is the method wherein the integrin receptor antagonizing effect is an avp5 antagonizing effect.

More specifically, the avp5 antagonizing effect is selected from inhibition of restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, tumor growth, or metastasis.

Illustrating the invention is the method wherein the integrin receptor antagonizing effect is a dual avp3/av5 antagonizing effect. More particularly, the dual av3/cav5 antagonizing effect is selected from inhibition of bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, viral disease, tumor growth, or metastasis.

Illustrating the invention is the method wherein the integrin receptor antagonizing effect is an avp6 antagonizing effect.

More particularly, the av36 antagonizing effect is selected from inhibition of angiogenesis, inflammatory response, or wound healing.

Illustrating the invention is the method wherein the avp3 antagonizing effect is selected from inhibition of bone resorption, WO 99/30713 PCT/US98/26485 inhibition of restenosis, inhibition of angiogenesis, inhibition of diabetic retinopathy, inhibition of macular degeneration, inhibition of atherosclerosis, inflammation, viral disease, or inhibition of tumor growth or metastasis. Preferably, the av33 antagonizing effect is the inhibition of bone resorption.

More particularly illustrating the invention is a pharmaceutical composition comprising any of the compounds described above and a pharmaceutically acceptable carrier. Another example of the invention is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier. Another illustration of the invention is a process for making a pharmaceutical composition comprising conibining any of the compounds described above and a pharmaceutically acceptable carrier.

Further illustrating the invention is a method of treating and/or preventing a condition mediated by antagonism of an integrin receptor in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds described above. Preferably, the condition is selected from bone resorption, osteoporosis, restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, viral disease, cancer, tumor growth, and metastasis. More preferably, the condition is selected from osteoporosis and cancer. Most preferably, the condition is osteoporosis.

More specifically exemplifying the invention is a method of eliciting an integrin antagonizing effect in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions described above. Preferably, the integrin antagonizing effect is an avp3 antagonizing effect; more specifically, the avp3 antagonizing effect is selected from inhibition of bone resorption, inhibition of restenosis, inhibition of atherosclerosis, inhibition of angiogenesis, inhibition of diabetic retinopathy, inhibition of macular degeneration, inhibition of inflammation, inhibition of viral disease, or inhibition of tumor growth or metastasis. Most preferably, the avp3 56- WO 99/30713 PCT/US98/26485 antagonizing effect is inhibition of bone resorption. Alternatively, the integrin antagonizing effect is an (av35 antagonizing effect, an avp6 antagonizing effect, or a mixed avP3, av35, and avp6 antagonizing effect. Examples of avp5 antagonizing effects are inhibition of restenosis, atherosclerosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, viral disease, or tumor growth. Examples of dual avp6 antagonizing effects are inhibition of angiogenesis, inflammatory response and wound healing.

Additional examples of the invention are methods of inhibiting bone resorption and of treating and/or preventing osteoporosis in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds or any of the phafmnaceutical compositions described above.

Additional illustrations of the invention are methods of treating hypercalcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, immobilizationinduced osteopenia, and glucocorticoid treatment in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions described above.

More particularly exemplifying the invention is the use of any of the compounds described above in the preparation of a medicament for the treatment and/or prevention of osteoporosis in a mammal in need thereof. Still further exemplifying the invention is the use of any of the compounds described above in the preparation of a medicament for the treatment and/or prevention of bone resorption, tumor growth, cancer, restenosis, atherosclerosis, diabetic retinopathy, macular degeneration, inflammation, viral disease, and/or angiogenesis.

Also exemplifying the invention are compositions further comprising an active ingredient selected from the group consisting of an organic bisphosphonate or a pharmaceutically acceptable salt or ester thereof, an estrogen receptor modulator, -57- WO 99/30713 PCT/US98/26485 a cytotoxic/antiproliferative agent, a matrix metalloproteinase inhibitor, an inhibitor of epidermal-derived, fibroblast-derived, or platelet-derived growth factors, an inhibitor of VEGF, an inhibitor ofFlk-1/KDR, Flt-1, Tck/Tie-2, or Tie-1, a cathepsin K inhibitor, and a prenylation inhibitor, such as a farnesyl transferase inhibitor or a geranylgeranyl transferase inhibitor or a dual farnesyl/geranylgeranyl transferase inhibitor; and mixtures thereof.

(See, B. Millauer et al., "Dominant-Negative Inhibition of Flk-1 Suppresses the" Growth of Many Tumor Types in Vivo", Cancer Research, 56, 1615-1620 (1996), which is incorporated by reference herein in its entirety).

Preferably, the active ingredient is selected from the group consisting of: an organic bisphosphonate or a pharmaceutically acceptable salt or ester thereof, an estrogen receptor modulator, and a cathepsin K inhibitor, and mixtures thereof.

Nonlimiting examples of such bisphosphonates include alendronate, etidronate, pamidronate, risedronate, ibandronate, and pharmaceutically acceptable salts and esters thereof. A particularly preferred bisphosphonate is alendronate, especially alendronate monosodium trihydrate.

Nonlimiting examples of estrogen receptor modulators include estrogen, progesterin, estradiol, droloxifene, raloxifene, and tamoxifene.

Nonlimiting examples of cytotoxic/antiproliferative agents are taxol, vincristine, vinblastine, and doxorubicin.

Cathepsin K, formerly known as cathepsin 02, is a cysteine protease and is described in PCT International Application Publication No. WO 96/13523, published May 9, 1996; U.S. Patent No. 5,501,969, issued March 3, 1996; and U.S. Patent No. 5,736,357, issued April 7, 1998, -58- WO 99/30713 PCT/US98/26485 all of which are incorporated by reference herein in their entirety.

Cysteine proteases, specifically cathepsins, are linked to a number of disease conditions, such as tumor metastasis, inflammation, arthritis, and bone remodeling. At acidic pH's, cathepsins can degrade type-I collagen. Cathepsin protease inhibitors can inhibit osteoclastic bone resorption by inhibiting the degradation of collagen fibers and are thus useful in the treatment of bone resorption diseases, such as osteoporosis.

The present invention is also directed to combinations of the compounds of the present invention with one or more agents useful in the prevention or treatment of osteoporosis. For example, the compounds of the instant invention may be effectively administered in combination with effective amounts of other agents such as an organic bisphosphonate; an estrogen receptor modulator, or a cathepsin K inhibitor.

Additional illustrations of the invention are methods of treating tumor growth in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound described above and one or more agents known to be cytotoxic/antiproliferative. Also, the compounds of the present invention can be administered in combination with radiation therapy for treating tumor growth and metastasis.

In addition, the integrin av33 antagonist compounds of the present invention may be effectively administered in combination with a growth hormone secretagogue in the therapeutic or prophylactic treatment of disorders in calcium or phosphate metabolism and associated diseases. These diseases include conditions which can benefit from a reduction in bone resorption. A reduction in bone resorption should improve the balance between resorption and formation, reduce bone loss or result in bone augmentation. A reduction in bone resorption can alleviate the pain associated with osteolytic lesions and reduce the incidence and/or growth of those lesions. These diseases include: osteoporosis (including estrogen deficiency, immobilization, glucocorticoid induced and senile), osteodystrophy, Paget's disease, myositis ossificans, Bechterew's disease, malignant hypercalcemia, metastatic bone disease, periodontal disease, -59- WO 99/30713 PCT/US98/26485 cholelithiasis, nephrolithiasis, urolithiasis, urinary calculus, hardening of the arteries (sclerosis), arthritis, bursitis, neuritis and tetany. Increased bone resorption can be accompanied by pathologically high calcium and phosphate concentrations in the plasma, which would be alleviated by this treatment. Similarly, the present invention would be useful in increasing bone mass in patients with growth hormone deficiency. Thus, preferred combinations are simultaneous or alternating treatments of an avp3 receptor antagonist of the present invention and a growth hormone secretagogue, optionally including a third component comprising an organic bisphosphonate, preferably alendronate monosodium trihydrate.

In accordance with the method of the present invention, the individual com'ponents of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment, and the term "administering" is to be interpreted accordingly. It will be understood that the scope of combinations of the compounds of this invention with other agents useful for treating integrin-mediated conditions includes in principle any combination with any pharmaceutical composition useful for treating osteoporosis.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. Likewise, they may also be administered in intravenous (bolus or infusion), intraperitoneal, topical ocular eyedrop), subcutaneous, intramuscular or transdermal patch) form, all using forms well known to those of ordinary skill in the pharmaceutical WO 99/30713 PCT/US98/26485 arts. An effective but non-toxic amount of the compound desired can be employed as an av33 antagonist.

The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician, veterinarian or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

Oral dosages of the present invention, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 to mg/kg/day, and most preferably 0.1 to 5.0 mg/kg/day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably, from about 1 mg to about 100 mg of active ingredient. Intravenously, the most preferred doses will range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion.

Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.

Furthermore, preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are -61- WO 99/30713 PCT/US98/26485 typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as 'carrier' materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as' ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or betalactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted -62- WO 99/30713 WO 9930713PCT/US98/26485 1 with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers usefuil in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymners of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cros slinked or amphipatbic block copolymers of hydrogels.

In the schemes and examples below, various reagent symbols and abbreviations have the following meanings: .0 AcOH: Acetic acid.

BH3 DMS: Borane dimethylsulfide.

BOC(Boc): t-Butyloxycarbonyl.

BOP: Benzotriazol- 1-yloxytris(dimethylamino)phosphonium hexafluorophosphate.

5 CBZ(Cbz): Carbobenzyloxy or berizyloxycarbonyl.

CDI: Carbonyldiiniidazole.

CH

2 Cl 2 Methylene chloride.

CH3CN: Acetonitrile CHC13: Chloroform.

I

DEAD:

DIAD:

DIBAH or

DJBAL-H:

DIPEA:

DMAP:

DME:

DMF:

DMSO:

DPFN:

EDC:

EtOAc: EtOH: HOAc:

HOAT:

HOBT:

Diethyl azodicarboxylate.

Diisopropyl azoclicarboxylate.

Diisobutylailuminum hydride.

Diisopropylethylamine.

4-Dimethylaminopyridine.

1, 2-Dimethoxyethane.

Dimethylformamide.

Dimethylsulfoxide.

3,5-Dimethyl-1-pyrazolylformamidine nitrate.

3-Dimethylaminopropyl)-3-ethylcarb odiimide HCI Ethyl acetate.

Ethanol.

Acetic acid.

1-Hydroxy-7-azabenzotriazole 1-Hydroxybenzotriazole.

-63- WO 99/30713 PCT/US98/26485 IBCF: Isobutylchloroformate LDA: Lithium diisopropylamide.

MeOH: Methanol.

MMNG 1,1-methyl-3-nitro- 1-nitrosoguanidine NEt3: Triethylamine.

NMM: N-methylmorpholine.

PCA'HC1: Pyrazole carboxamidine hydrochloride.

Pd/C: Palladium on activated carbon catalyst.

Ph: Phenyl.

pTSA p-Toluenesulfonic acid.

TEA: Triethylamine.

TFA: Trifluoroacetic acid.

THF: Tetrahydrofuran.

TLC: Thin Layer Chromatography.

TMEDA: N,N,N',N'-Tetramethylethylenediamine.

TMS: Trimethylsilyl.

The novel compounds of the present invention can be prepared according to the procedure of the following schemes and examples, using appropriate materials and are further exemplified by the following specific examples. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The following examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless otherwise noted.

The following Schemes and Examples describe procedures for making representative compounds of the present invention.

Moreover, by utilizing the procedures described in detail in PCT International Application Publication Nos. W095/32710, published 7 December 1995, and W095/17397, published 29 June 1995, both of which are incorporated by reference herein in their entirety, in conjunction with the disclosure contained herein, one of ordinary skill in the art can -64- WO 99/30713 PCT/US98/26485 readily prepare additional compounds of the present invention claimed herein. Additionally, for a general review describing the synthesis of 3-alanines which can be utilized as the C-terminus of the compounds of the present invention, see Cole, Recent Stereoselective Synthetic Approaces to P-Amino Acids, Tetrahedron, 1994, 50, 9517-9582; Juaristi, E, et al., Enantioselective Synthesis of P-Amino Acids, Aldrichimica Acta, 1994, 27, 3. In particular, synthesis of the 3-methyl--alanine is taught in Duggan, M.F. et al., J. Med. Chem., 1995, 38, 3332-3341; the 3ethynyl-P-alanine is taught in Zablocki, et al., J. Med. Chem., 1995, 38, 2378-2394; the 3-(pyridin-3-yl)-p-alanine is taught in Rico, J.G. et al., J. Org. Chem., 1993, 58, 7948-7951; and the 2-amino- and 2-tosylamino-palanines are taught in Xue, C-B, et al., Biorg. Med. Chem. Letts., 1996, 6, 339-344. Tih references described in this paragraph are all also incorporated by reference herein in their entirety.

WO 99/30713 WO 9930713PCTIUS98/26485 SCREME I 7

CHO

Ph 3

PCHCO

2 Et

CH

2 01 2

H

Ph,N.,,,Ph Me TMSCI, THF 2. n~uLi, THF 3. H 2 0 1. Pd(OH) 2

H

2 EtOH, HOAc, H 2 0 2. HCI, ether

*HCI

1-4 -66- WO 99/30713 PCT/US98/26485 Ethyl 3-fluorocinnamate (1-2) To a solution of 3-fluorobenzaldehyde 1-1 (18.16 g, 146 mmol) in dichloromethane (500 mL) was added ethyl (triphenylphosphoranylidene)acetate (61.2 g; 176 mmol) and the resulting solution was stirred at room temperature for 18 hr. After evaporation of the solvent, the residue was swirled with ether/hexane and filtered. The filtrate was concentrated and then purified on a plug of silica gel eluting with hexane/EtOAc 9:1. Removal of the solvent afforded the title compound 1-2 as an oil trans) which was used without further purification in the next step.

1H NMR (CDC13): 6 1.36 (3H, 4.28 (2H, 6.43 (1H, 7.08 (1H, m), 7.2-7.4 (3H, 7.64 (1H, d).

N-Benzvl-(R)-a-methvlbenzvl-3(S)-fluorophenvl-f3-alanine ethyl ester (1-3) To a solution of N-benzyl-(R)-a-methylbenzylamine (33.4 g, 158 mmol) in THF (450 mL) at 0°C was added n-butyllithium (1.6M in hexanes; 99 mL, 158 mmol). The dark violet solution was stirred at 0 C for 30 minutes, cooled to -78 0 C and the ester 1-2 (29.2 g, 150 mmol) in THF (100 mL) was added over 5 minutes. The resulting solution was stirred at -78 0 C for 1 hr, then warmed to room temperature. After 2 hrs, the mixture was poured into water and extracted with EtOAc, washed with water, then brine, dried and concentrated in vacuo to give an oil. Column chromatography (silica gel; hexane/EtOAc 1:1 then pure EtOAc) gave the title compound 1-3.

1H NMR (CDC13): 6 1.06 (3H, 1.28 (3H, 2.52 (1H, dd), 2.62 (1H, dd), 3.66 (1H, 3.72 (1H, 3.95 (2H, 4.44 (1H, dd), 6.95 (1H, 7.1-7.5 (13H, m).

3(S)-Fluorophenvl-f-alanine ethyl ester hvdrochloride (1-4) A solution of the N-benzyl-(R)-a-methylbenzylamine derivative 1-3 (28.2 g, 69.6 mmol) in ethanol (300 mL), acetic acid (30 mL) and water (3 mL) was degassed with argon for 30 minutes. Pd(OH)2 on carbon (20% dry weight; 2.6 g) was added and the mixture then stirred under a hydrogen atmosphere (balloon) for 2 hours. The mixture was filtered through celite and the solvent removed in vacuo to give an oil.

-67- WO 99/30713 PCT/US98/26485 This oil was dissolved in 200 mL ether and to this solution was added mL IN HC1 in ether to yield a precipitate. Filtration and washing the solid with ether/hexane then gave the title compound 1-4 as a white solid.

1H NMR (CD30D): 5 1.21 (3H, 3.0-3.2 (2H, 4.16 (2H, 4.76 (1H, t), 7.2-7.35 (3H, 7.5 (1H, m).

(L

-68- WO 99/30713 WO 9930713PCTIUS98/26485 SCIHEME 2 0 '11 CO 2 Et ethylene glycol, pTSA, toluene, ref lux C0 2

R

22a) pivaloyl chloride, NEt 3

THEF

b) Li oxazolidinone 0 0

N

2-3 0 0 Ia) LiN(TMS) 2

THF

b) butenyl-4-trif late 0 0( 2-4

X=CH

2 0N 0 03, ~l 2a, sudan Ill, 0 0 0H 2 C1 2 69- WO 99/30713 WO 9930713PCT/US98/26485 SCHEME 2 (CONTINUED) 0O N 0 o 0

HCI*H

2

N,

Na(OAc) 3 BH, NEt 3

H

dlichioroethane 1-4 OP OD

N

C0 2 Et TsOH, acetone, reflux

N

1" CO 2 Et 2-7 7

F

proline,C ethanol, reflux N N WO 99/30713 WO 9930713PCTIUJS98/26485 SCHEME 2 (CONTINUED)

CO

2 Et 11%PCI/C, ethanol,

H

2

CO

2 Et 1N NaOH, ethanol and 2,-1)

HI

N N N C0 2

H

H 0H

F

-71- WO 99/30713 PCT/US98/26485 5-(2-Methvl-[1,31dioxolan-2-vl)-pentanoic acid (2-2) A mixture of ketone 2-1 (18 g, 105 mmol), ethylene glycol (3.2 ml, 110 mmol), p-TSA (50 mg, 0.2713 mmnol) and toluene (300 mL) was heated to reflux with azeotropic removal of water for 24 hours. The reaction mixture was diluted with EtOAc and then washed with sat.

NaHC03, brine, dried (MgS04), and concentrated. The residue was dissolved in EtOH (200 ml) and then treated with 1N NaOH (120 ml, 120 mmol). After 2 h, the reaction was poured into 600 mL 2:1 Et20/10% KHS04. The organic portion was separated, washed with brine, dried (MgSO4) and concentrated to give acid 2-2 as a colorless oil.

1H NMR (300 MHz, CDC13) 8 3.93 4H), 2.36 2H), 1.63 4H), 1.46 2H), 1.31 3H).

3-r5-(2-Methyl-r1,31dioxolan-2-vl)-pentanovl1-oxazolidin-2-one (2-3) To a stirred solution of 2-2 (16.0 g, 85.5 mmol), NEt3 (13.1 ml, 94.1 mmol) and THF (400 mL) at -78 0 C was added pivaloyl chloride (11.6 ml, 94.1 mmol). The mixture was warmed to 0 C for 1.0 h and then recooled to -78 0 C. To a stirred solution of 2-oxazolidinone (9.3g, 106.9 mmol) and THF (200 ml) at -78 0 C was added nBuLi (43.0ml, 106.9 mmol, 2.5M in hexanes) dropwise over 10 minutes. After 20 minutes, the lithium reagent was transferred to the mixed anhydride via cannula.

After 10 minutes, the reaction was warmed to 0°C for 1.0h. The mixture was diluted with ethyl acetate, washed with sat. NaHCO3, brine, and dried over MgS04. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 40%-50% EtOAc/hexanes) to give 2-3 as a colorless foam.

TLC Rf 0.19 (silica, 40% EtOAc/hexanes) 1H NMR (300 MHz, CDC13) 6 4.41 J=8.1 Hz, 2H), 4.02 J=8.1 Hz, 2H), 3.93 4H 3.93 J=7.3 Hz, 2H), 1.66 4H), 1.48 2H), 1.31 (s, 3H).

-72- WO 99/30713 PCT/US98/26485 3-(2-[3-(2-Methyl-[1,3]dioxolan-2-yl)-propyl]-hex-5-enoyl)-oxazolidin- 2-one (2-4) To a stirred solution of 2-3 (3.0 g, 11.7 mmol) and THF (125 mL) at -78 0 C was added NaN(TMS)2 (15.2 mL, 15.2 mmol, 1.0 M in THF) dropwise over 20 minutes. Butenyl-4-triflate (5.0 mL, 29.2 mmol) was added dropwise; after 1 h, the reaction was warmed to 0 C. After 1 h, the reaction was diluted with EtOAc, washed with sat. NaHC03, brine, dried (MgS04) and concentrated. Flash chromatography (silica, EtOAc/ hexanes) gave 2-4 as an yellow oil.

TLC Rf 0.28 (silica, 50% EtOAc/hexanes) 1H NMR (300 MHz, CDC13) 6 5.80 1H), 5.00 2H), 4.40 2H), 4.02 2H), 3.92 4H), 2.40-1.35 11H), 1.30 3H).

7-(2-Methyl-[ 1,3]dioxolan-2-yl)-4-(2-oxo-oxazolidine-3-carbonyl)heptanal To a stirred solution of 24 (1.8 g, 5.8 mmol), sudan III mg) and CH2C12 (150 mL) at -78 0 C under argon was bubbled ozone until the red solution changed to yellow-orange. The solution was purged with argon for 30 minutes. PPh3 (2.26 g, 8.7 mmol) was added followed by the removal of the cooling bath. After 1.5 h, the reaction was concentrated. Flash chromatography (silica, 20%-50% EtOAc/hexanes) gave 2-5 as a yellow solid.

TLC Rf 0.17 (silica, 50% EtOAc/hexanes) 1H NMR (300 MHz, CDC13) 6 9.74 1H), 4.43 2H), 4.03 2H), 3.91 4H), 3.80 3.04 1H), 2.48 2H), 2.10-1.40 8H), 1.29 (s, 3H).

3(S)-(3-Fluoro-phenyl)-3-{2-oxo-[3-(2-methyl-[1,3]dioxolan-2-yl)propvll- piperidin-1-vl}-propionic acid ethyl ester (2-6) A mixture of 2-5 (600 mg, 1.0 mmol), 1-4 (240 mg, 1.0 mmol), Na(OAc)3BH (313 mg, 1.5 mmol) and NEt3 (0.28 mL, 2.0 mmol) in DCE mL) was stirred for 24 h. The mixture was diluted with ethyl acetate, washed with 10% K2C03, brine, and dried over MgSO4. Following evaporative removal of the solvent, the residue was chromatographed -73- WO 99/30713 WO 99/07 13PCTIUS98/26485 (silica gel, 50:35:14:1- hexanes/ chloroform! ethyl acetate! MeGH) to give 2-6 as a yellow solid.

TLC Rf 0.53 (silica, 70:25:5 chloroform! ethyl acetate! MeGH) 1H N1VMR (300 MHz, CDCl3) 5 7.30 (in, 1H), 7.07 (mn, 1H), 6.98 (m 3H), 6.35 (in, 0.5H), 6.23 (mn, 0.5H), 4.12 J=7 Hz, 2H), 3.92 (mn, 4H), 3.20 (mn, 1H), 2.95 (mn, 3H), 2.38 (mn, 1H),2.00-1.40 (mn, 8H), 1.30 3H), 1.22 J=7 Hz, 3H).

3 (S)-(3-Fluorophenyl)-3-[2-oxo-3-(4-oxo-pentyl)-piperidin- l-yl]- Uropionic acid ethyl ester (2-7) A solution of 2-6 (500 mg, 1.10 minol), p-TSA (10 ing) and acetone (50 mL) was heated at reflux for 4 h. The cooled reaction mixture was diluted with EtOAc and then washed with sat. NaHCO3 and brine, dried (MgSO4), and concentrated to afford 2-71 as a yellow oil.

1H NMZR (300 NMz, CDCl3) 5 7.30 (in, 1H), 7.06 (mn, 1H), 6.98 (in, 2H), 6.32 (mn, 0.5H), 6.20 (in, 0.5H1), 4.12 (qi, J=7Hz, 2H), 3.20 (in, 1H), 2.95 (mn, 3H), 2.45 (mn, 2H), 2.33 (in, 1H), 2.14 3H), 2.00-1.40 (mn, 8H), 1.22 J=7 Hz, 3H).

3(S)-(3-Fluorophenyl)-3-[3-(3-[1,8]naphthyridin-2-yl-propyl)-2oxo-ineridin-l-vll-Drorionic acid ethyl ester (2-8) A mixture of 2-7 (450 ing, 1.2 mmiol), 2-amino-3forinylpyridine (145 ing, 1.2 minol; for prep., see JOG 1983,48, 3401) and proline (137 ing, 1.2. mmrol) in absolute ethanol (20 inL) was heated at reflux for 12 h. Following evaporative removal of the solvent, the residue was chroinatographed (silica gel, 50% ethyl acetate! chloroform to 70:25:5 chloroform/ethyl acetate/MeOH) to give 2-8 as a yellow oil.

TLC Rf 0.34 (70:25:5 chloroform/ethyl acetate/MeON).

1H1 N.MR (300 MHz, CDCl3) 5 9.08 (mn, 1H), 8.16 (dd, J=2.0 Hz, 8.0 Hz 1H1), 8.11 Kd J=8.3 Hz, 1H1), 7.42 (mn, 2H), 7.06 (in, 1H), 6.97 (in, 2H), 6.35 (in, 6.20 (in, 0.5H1), 4.11 (mn, 2H), 3.20-2.80 (in, 5H), 2.40 (mn, 1H), 2.10- 1.40 (mn, 8H), 1.19 (in, 3H).

-74- WO 99/30713 WO 9930713PCTIUS98/26485 3(S)-(3-Fluorophenyl)-3-(2-oxo-3-[3-(5 ,6,7,8-tetrahydro-[1,8]naphthvidin- 2-vl-)-rorwl-ip)eri din- 1 -vl)-iuro~i onic acid ethyl ester (2-9) A mixture of 2- (400 ing, 0.86 mmol) and 10% Pdicarbon (1300 ing) in EtOH (10 mL) was stirred under a balloon of hydrogen for 6 h. Following filtration and evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:25:5 chloroform/ethyl acetatefMeOH) to give 2-9 as a yellow oil.

TLC Rf 0.21 (70:25:5 chloroform/ethyl acetate/MeOH).

1H NMR (300 MHz, CDCl3) 5 7.29 (mn, 7.05 (mn, 2H), 6.98 (in, 2H), 6.33 (mn, 1H), 6.30 (mn, 0.5H), 6.20 (in, 0.5H), 4.76 (bs, 1H), 4.10 (in, 2H), 3.40 (in, 2H), 3.20 (mn, 1H), 3.00-2.90 (in, 3H), 2.70 J=6.3 Hz, 2H), 2.55 (mn, 2H), 2.35 (in, 1H), 2.00- 1.40 (in, 8H), 1.23 J=7Hz, 3H).

3(S)-(3-Fluorophenyl)-3-(2-oxo-3(R or S)-113-(5 ,6,7,8-tetrahydro- 8]naphthyriclin-2-yl)-propyl]-piperidin- 1-yl)-propionic acid and 3(S)-(3-fluorophenyl)-3-(2-oxo-3( S or ,6,7,8-tetrahydro- 8]naphthyridin-2-yl)-propyl]-piperidin- 1-yl)-propionic acid (2-10 and 2-11) To a solution of 2- (300 ing, 0.6614 mnmol) in EtOH (3 mL) was added 1N NaOH (0.725 ml, 0.725 mmol). After stirring for 1 h, the solvents were evaporated and the residue was chroinatographed (silica gel, 25:10:1:1 15:10:1:1 ethyl acetatefEtOHlwater/NT{40H) to give 2-10 and 2-11 as pure diastereoineric white solids.

TLC Rf 0.62 (isomer A) (10: 10: 1: 1 ethyl acetatelEtOH/water/NH4OH).

TLC Rf 0.51 (isomer B) (10: 10: 1: 1 ethyl acetate/EtOH-1waterfNH4OH).

1H NMR (300 MHz, CD3OD, Isomer A) 5 7.46 J=7 Hz, 1H), 7.37 (in, 1H), 7.15 (in, 1H), 7.10 (in, 7.03 (in, 1H), 6.50 J=7 Hz, 6.43 (in, 1H), 3.48 (in, 2H), 3.36 (in, 2H), 3.00 (in, 1H), 2.90 (in, 2H), 2.70 (mn, 2H), 2.80-2.55 (in, 3H), 2.12-1.40 (in, 1H NMR (300 MHz, CD3OD, Isomer B) 5 7.40 J=7 Hz, 1H), 7.34 (in, 1H), 7.15 (in, 1H), 7.10 (in, 7.00 (in, 1H), 6.50 J=7 Hz, 5.63 (mn, 1H), 3.45 (in, 2H), 3.36 (in, 2H), 3.15 (in, 2H), 2.82 (in, 1H), 2.78 (in, 2H), 2.63 (in, 2H), 2.47 (mn, 1H), 2.00-1.50 (in, WO 99/307 13 PTU9/68 PCT[US98/26485 SCHEME 3

OH

Br QEt "---OEt NaH, DMVF 3-1 Wi 3-2 PPA, PhMe j Ethyl Acrylate, Pd(OAc) 2

DMF

3-3 Me PhN'Ph

H

nBuLi, THF Pd(OH) 2

H

2 H2N C02D I-Bromo-3-(2 .2-diethoxv-ethoxv)-benzene (3-2) To a suspension of NaH (2.77 g, 115.6 mmol) in DMF (100 mL) at 0 0 C was added a solution of 3-bromophenol 3-1 in DMF (40 mL) -76- WO 99/30713 PCT/US98/26485 over 40 min. After the addition was complete, the solution was stirred for an additional 30 min. The solution was then treated with neat bromoacetaldehyde diethyl acetal (17.36 g, 115.6 mmol). The solution was heated at 100 0 C for 8 h, cooled to room temperature, and extracted with Et20 (3 x 200 mL). The combined organic extracts were washed with 10% aq. NaOH (100 mL) and brine (100 mL), dried over MgS04, filtered and concentrated to give 3-2 as a yellow oil.

TLC Rf 0.4 (10% ethyl acetate/hexanes).

1 H NMR (300 MHz, CDC13) 5 7.19-7.05 3H), 6.85 1H), 4.81 1H, J=6.8 Hz), 3.99 2H, J=6.8 Hz), 3.71 4H), 1.22 6H, J=7.1 Hz) ppm.

6-Bromo-benzofuran (3-3) To a solution of the acetal 3-2 in toluene (200 mL) was added polyphosphoric acid (20 The biphasic mixture was heated to 100°C and stirred at this temperature for 4 h. The mixture was cooled to room temperature, poured onto ice, and extracted with Et20 (2 x 200 mL). The combined organic extracts were washed with saturated aq. NaHC03 and brine. The solution was dried over MgSO4, filtered, and concentrated.

The residue was purified by flash chromatography (100% hexanes) to give the product 3-3 as a yellow oil.

TLC Rf 0.3 (100% hexanes).

1H NMR (300 MHz, CDC13) 5 7.68 1H), 7.60 1H, J=2.1 Hz), 7.46 (d, 1H, J=8.4 Hz), 7.36 (dd, 1H, J=8.1, 1.5 Hz), 6.75 (dd, 1H, J=7.1, 0.9 Hz) ppm.

3-(Benzofuran-6-vl)-acrylic acid ethyl ester (3-4) A mixture of the 6-bromo-benzofuran 3-3 (1.74 g, 8.79 mmol), ethyl acrylate (1.09 g, 10.98 mmol), Pd(OAc)2 (0.099 g, 0.44 mmol), tri-o-tolylphosphine (0.268 g, 0.880 mmol), and sodium acetate (3.60 g, 43.9 mmol) in DMF (10 mL) was heated to 100 0 C in a sealed tube for 4 h. The mixture was cooled to room temperature, diluted with water, and extracted with Et20 (2 x 40 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (10% ethyl acetate/hexanes) to give the ester 3-4 as an off-white solid.

-77- WO 99/30713 PCT/US98/26485 TLC Rf 0.3 (10% ethyl acetate/hexanes).

1H NMR (300 MHz, CDC13) 5 7.78 1H, J=15.9 Hz), 7.68 1H, J=2.4 Hz), 7.66 1H), 7.59 1H, J=8.4 Hz), 7.43 (dd, 1H, J=9.0, 1.5 Hz), 6.78 1H), 6.47 1H, J=15.9 Hz), 4.27 2H, J=7.2 Hz), 1.34 3H, J=7.2 Hz) ppm.

3(S)-Benzofuran-6-yl-3-[benzyl-(l(R)-phenyl-ethyl)-amino]-propionic acid ethyl ester A solution of N-benzyl-a-(R)-methylbenzylamine (1.32 g, 6.30 mmol) in THF (25 mL) at 0°C was treated with n-BuLi (2.52 mL of a 2.5 M soln in hexanes). The resulting solution was stirred at 0 C for 30 min and then cooled to -780C. A solution of acrylate 34 (0.681 g, 3.15 mmol) in THF (5 mL) was added. After stirring for 15 min at -78 satd. aq.

NH4C1 soln (5 mL) was added and the cold bath removed. The mixture was warmed to room temperature and extracted with Et20 (2 x 40 mL).

The combined organic extracts were washed with brine (30 mL), dried over MgS04, filtered, and concentrated. The residue was purified by flash chromatography (10% ethyl acetate/hexanes) to give the 3-aminoester 3-5 as a yellow oil.

TLC Rf 0.8 (10% ethanol/dichloromethane).

1 H NMR (300 MHz, CDC13) 5 7.58 3H), 7.41 2H), 7.22 9H), 7.59 1H), 4.58 1H), 4.05 1H), 3.91 2H, J=7.1 Hz), 3.72 2H), 2.62 2H), 1.21 3H, J=7.2 Hz), 1.03 3H, J=7.1 Hz) ppm.

3(S)-Amino-3-(2,3-dihydro-benzofuran-6-yl)-propionic acid ethyl ester (3-6) A mixture of the dibenzylamine 3-5 (1.19 g, 2.78 mmol) in (26 mL/3 mL/1.0 mL) was degassed with argon and treated with Pd(OH)2 (1.19 The mixture was placed under 1 atm of H2. After stirring for 18 h, the mixture was diluted with EtOAc, and filtered through celite. The filtrate was concentrated and the residue purified by flash chromatography (10% ethyl acetate/dichloromethane) to give the ester 6 as a white solid.

TLC Rf 0.25 (10% ethanol/dichloromethane).

-78- WO 99/30713 WO 9930713PCTIUS98/26485 1 H NMR (300 MHz, CD3OD) as the trifluoroacetate salt: 5 7.25 1H, J=8.1 Hz), 6.88 (in, 1H), 7.66 1H), 6.82 1H), 4.58 (mn, 3H), 4.12 (mn, 2H), 3.30 (mn, 1H), 3.19 (mn, 2H), 2.98 (mn, 2H), 1.11 3H, J=7.2 Hz) ppm.

SCHME 4 OH HI-HK00H3 IBOF, NEt 3 0H 0 OC 0H3 0 0H3 ethylene glycol TsOH, heat -X-j ,CH3 0 0 CH3 4-2

DIBAL

JH

O 0 4-3 HCI*H2N Et 0 NaB(OAc) 3

H

M~

3 0 N% BOCP9 N o~ QJ H DMAP (cat.) 0 OEt acetone, TsOH 0 0 heat tBuO 0Q 0 N"-""QEt tBuo 0 79- WO 99/30713 WO 9930713PCTIUS98/26485

NNH

2 praline, EtOH N tBuCK 0 y 4-7 0

NO

2

H

2 EtQH N- tBucK I oEt N N H 0 1) NaOH, then HCI 2) EDO, HOBT, NEt 3

OH

3 USN.I tOG. 0H 3 N NNN H 0 4-9

DIBAL

N- tBu0ly50 N N H 0 4-9A 0 NaONBH 3

I

NaQAc 0 4-10 WO 99/30713 PCT/US98/26485 HC1 (g) 4-10 H 0 NNr -N OEt H H °3 HCI 4-11 R J 'a N0 2

H

4-12 iPr 2 NEt NaOH 4-13 4-Oxo-pentanoic acid methoxv-methyl-amide (4-1) To a stirred solution of levulinic acid (30 g, 0.258 mol) in 850 mL CHC13 at 0°C was added triethylamine (43.2 mL, 0.310 mol), followed by isobutyl chloroformate (37 mL, 0.284 mol) over 15 minutes. After minutes, triethylamine (57.6 mL, 0.413 mol) was added, followed by N,Odimethylhydroxylamine hydrochloride (37.8 g, 0.387 mol) in 5 portions over 5 minutes. Vigorous bubbling ensued, and the mixture was allowed to warm to RT and stir for 1 h. The mixture was reduced to a moist solid by rotary evaporation under reduced pressure, slurried in -81- WO 99/30713 PCT/US98/26485 500 mL EtOAc, washed with 10% K2CO3, brine, and dried over Na2SO4.

Evaporative removal of the solvent gave 4-1 as a yellow oil.

TLC Rf= 0.42 (silica, 1:1 chloroform /ethyl acetate).

1 H NMR (300 MHz, CDC13) 5 3.74 3H), 3.18 3H), 2.65-2.95 4H), 2.21 3H).

N-methoxv-N-methvl-3-(2-methyl-r1.31dioxolan-2-vl)-propionamide (4-2) To a solution of 4-1 (38 g, 0.239 mol) in 500 mL benzene was added ethylene glycol (17.3 mL, 0.310 mol) and p-toluenesulfonic acid (1 The mixture was heated at reflux for 2 h with azeotropic removal of water. After cooling, the solution was washed with 200 mL sat.

NaHCO3, brine, and dried over Na2SO4. Evaporative removal of the solvent gave 4-2 as a yellow oil.

TLC Rf 0.62 (silica, ethyl acetate).

1 H NMR (300 MHz, CDC13) 5 3.95 4H), 3.68 3H), 3.17 3H), 2.51 2H, J=8 Hz), 2.00 3H, J=6 Hz) 1.33 3H).

3-(2-Methyl-1,31 dioxolan-2-vl)-propionaldehvde (4-3) To a solution of 5-2 (44.74 g, 0.22 mol) in 400 mL THF at -78 0 C was added DIBAL (264 mL 1 M in hexanes, 0.264 mol) over minutes. After stirring for 1 h, 350 ml of 1.0 M Rochelle's salt and 300 ml ether was added followed by the removal of the cooling bath. After stirring for 1 h, the organic portion was separated and dried over Na2S04. Evaporative removal of the solvent gave 4-3 as a colorless oil.

TLC Rf 0.80 (silica, ethyl acetate).

1 H NMR (300 MHz, CDC13) 5 9.73 1H), 3.50 1H, J=16 Hz), 2.61 (d, 1H, J=21 Hz), 2.48 1H), 2.07 1H, J= 7H), 1.33 3H).

r3-(2-Methvl-r1,31dioxolan-2-yl)-propylaminol-propionic acid ethyl ester (44) To a solution of 4-3 (10 g, 0.69 mmol) in 200 mL 1,2dichloroethane at 0 C was added beta-alanine ethyl ester hydrochloride (21 g, 0.138 mol), triethylamine (34 mL), and NaB(OAc)3H (20.5 g, 0.097 mol). The mixture was allowed to warm to RT and stir for 15 h. The mixture was evaporated to one-third its initial volume, diluted with EtOAc and then washed with 10% K2C03, brine, and dried over Na2SO4.

-82- WO 99/30713 PCT/US98/26485 Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:25:5 chloroform /ethyl acetate /methanol) to give 4-4 as a yellow oil.

TLC Rf 0.19 (silica, 70:25:5 chloroform /ethyl acetate /methanol).

{Tert-butoxvcarbonvl-[3-(2-methyl-[ 1,31dioxolan-2-vl)-propyll-amino}propionic acid ethyl ester To a solution of 4-4 (10 g, 0.041 mol) in 200 mL THF was added a trace of DMAP, 20 drops of triethylamine, and BOC20 (9.5 g, 0.045 mol). After 1 h, evaporative removal of the solvent gave 4-5 as a colorless oil.

TLC Rf 0.91 (silica, 70:25:10 chloroform /ethyl acetate /methanol).

1H NMR (300 MHz, CDC13) 5 4.15 2H, J=4 Hz), 3.93 4H), 3.46 (m, 2H), 3.22 2H), 2.58 2H), 1.61 4H), 1.48 9H), 1.28 6H).

rTert-butoxvcarbonvl-(4-oxo-pentvl)-amino-propionic acid ethyl ester (4-6) To a solution of 4-5 (13.9 g, 0.040 mol) in 100 mL acetone was added p-toluenesulfonic acid (.05 The mixture was heated at reflux for 2 h. After cooling, the mixture was evaporated to one-fifth its initial volume, diluted with EtOAc and then washed with sat. NaHCO3, brine, and dried over Na2SO4. Evaporative removal of the solvent gave 4-6 as a yellow oil.

TLC Rf 0.36 (silica, 30% ethyl acetate/hexane).

rTert-butoxvcarbonvl-(3- 1.81naphthridin-2-vl-propvl)-aminol-propionic acid ethyl ester (4-7) To a solution of 4-6 (12 g, 40 mmol), 2-amino-3formylpyridine (6.3 g, 52 mmol), proline (4.6 g, 40 mmol) and ethanol (300 mL) was heated at reflux for 15 h. After cooling and evaporation, the residue was chromatographed (silica gel, 1:1 chloroform /ethyl acetate) to give 4-7 as a yellow oil.

TLC Rf= 0.47 (silica, 70:25:5 chloroform /ethyl acetate /methanol) -83- WO 99/30713 PCT/US98/26485 1 H NMR (300 MHz, CDC13) 5 9.09 1H), 8.13 2H), 7.43 2H), 4.12 2H, 7 Hz), 3.42 4H), 3.03 2H), 2.48 2H), 2.16 2H), 1.42 9H), 1.22 3H).

{Tert-butoxvcarbonvl-[3-(5.6.7,8-tetrahvdro-r 1.81naphthvridin-2-vl)propyll-amino}-propionic acid ethyl ester (4-8) A solution of 5-7 (7.0 g, 18.1 mmol), 10% Pd/C (5 g) and ethanol (100 mL) was stirred under a balloon of hydrogen gas for 15 h.

Following filtration and evaporation, the residue was chromatographed (silica gel, 70:28:2 chloroform /ethyl acetate /methanol) to give 4-8 as a yellow oil.

TLC Rf 0.32 (silica, 70:28:2 chloroform /ethyl acetate /methanol) r(Methoxy-methvl-carbamovl)-ethvll-r3-(5.6.7,8-tetrahydror[1.8naphthvridin-2-vl)-propvll-carbamic acid tert-butvl ester (4-9) To a solution of 4-8 (5.6 g, 12.8 mmol) in ethanol (50 mL) was added NaOH (15 mL 1M solution in water,15 mmol). After stirring for 1 h, HC1 (15 mL 1M solution in water,15 mmol) was added, and the mixture evaporated to give an oily residue. The residue was evaporated from ethanol three times, and then from acetonitrile three times, producing a yellow crusty solid which was dried under a vacuum of <2 mm Hg for 2 h. This residue was then slurried in chloroform (5 mL) and acetonitrile (50 mL), and NMM (8.5 mL), NH,-dimethylhydroxylamine hydrochloride (2.5 g, 26 mmol), HOBT (1.7g, 13 mmol) and EDC (2.4 g, 13 mmol) were added. After stirring for 15 h, the mixture was evaporated to dryness, the residue slurried in EtOAc, washed with sat.

NaHCO3, brine, and dried over Na2S04. Evaporative removal of the solvent gave 4-9 as a yellow oil.

TLC Rf 0.20 (silica, 70:20:10 chloroform /ethyl acetate /methanol) 1 H NMR (300 MHz, CDC13) 5 7.05 1H, J= 8 Hz), 6.28 1H, J=8 Hz), 4.83 1H), 3.69 3H), 3.51 2H), 3.39 2H), 3.14 2H), 3.18 (s, 3H), 2.63 4H), 2.48 2H), 1.83 9H).

-84- WO 99/30713 WO 9930713PCT[US98/26485 fTert-butoxvcarbonvl-f 3-(5 .6.7 8-tetrahvdro-[ .1 8nauhthv-ridin-2-yl prop~vll- amino I-propi onaldehvd e (4-9A) To a stirred solution of 4- (12.8 minol) and THF (50 ml) at -78 0 C was added DIBAL (1.OM/hexanes, 15 ml, 15 mmol) dropwise over 20 minutes. After 1.0 hour, 20 ml of 1.0 M Rochelle's salt was added followed by the removal of the cooling bath. The mixture was stirred for hour and then diluted with Et2O. After 30 minutes of stirring, the organic portion was separated and dried over MgSO4. Evaporative removal of the solvent gave crude aldehyde 4-9A as a colorless oil.

TLC Rf 0.13 (silica, 75:2 0: 10 chloroform /EtOAc/MeOH).

3(S)-(2-{Tert-butoxvcarbonvl-[3-(5 .6.7 8-tetrahvdro-[1,81nanhthvridin-2vI )-nrouvl]-aminol-pron~vlamino)-3-(2,.3-dihvdro-benzofuran-6-vliuroipionic acid ethyl ester (4-10) A mixture of the crude aldehyde 4-9A (0.4 g, 1.15 inmol), 3-6 g, 1.5 mmol), powdered molecular sieves (1 sodium acetate (1 g) and 2-propanol (20 mL) was stirred for 30 minutes at 0 0 C. Then NaCNIBH3 (0.215 g, 3.5 mmol) was added. After 15 hours, to the reaction was added 10% KHS04 until pH-2, stirred 5 minutes, diluted with EtOAc and then adjusted to pH-12 with K2C03. The mixture was extracted with EtOAc and dried over MgSO4. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 1% [10:1:1 EtOHI NH40H/ H20]/ 99% 75:25:5 chloroform /EtOAcIMeOH) to give 4-10 as a yellow oil.

TLC Rf 0.19 (silica, 1% [10:1:1 EtOHI NTI4OHI H20]/ 99% 75:25:5 chloroform /EtOAc/MeOH) 1HNMR (300 MiHz, CDCl3) 5 7.10 (in, 2H),6.78 (in, 2H), 6.37 1H, J=7 Hz), 4.69 (hr s, 111), 4.47 2H, J= 7 Hz), 4.11 (mn, 2H), 3.95 1H, J= 7Hz), 3.38 (mn, 2H), 3.17 (in, 6H), 2.7-2.4 (in, 8H), 1.82 (in, 5H), 1.61 (in, 2H), 1.40 (mn, 9H), 1.21 3H, J= Hz).

85 WO 99/30713 PTU9/68 PCTIUS98/26485 3(S)-(2,3-dihvdro-benzofuran-6-vl)-3- f 2-oxo-3-[ 3-(5 .6,7 8-tetrahvdro- 1, 8 1naluhthvri din- 2-vl)--pronv ll -te trahvdro primi din- I1-vi I -pro pioni c acid ethyl ester (4-12) HOl gas was rapidly bubbled through a solution of 4-10 (0.3 g, 0.53 namol) in dichioromethane (10 ml) at 0 0 C for 10 minutes. After minutes, the solution was purged with argon for 30 minutes. The solution was concentrated to give the amine 4-li as a yellow solid.

To a stirred mixture of 4-11 (0.53 mmol) in CH2Gl2 (10 mL) and iPr2NEt (0.56 raL, 3.3 mnaol) was added para-njitrophenyl chloroforrnate (0.112 g, 0.55 rmnol). After 30 minutes, dioxane (10 naL) was added, and the mixture heated to 100 0 C, allowing the dichioromethane to evaporate.

After 12 h, the mixture was cooled, diluted with EtOAc, washed with 1 N NaOH, brine, and dried over MgSO4. Evaporative removal of the solvent gave 4-12 as a yellow oil.

TLC Rf 0.37 (silica, 70:20:10 chloroform /ethyl acetate /methanol) 3(S)-(2.3-dihvdro-benzofuran-6-vl)-3- f2-oxo-3-r3-(5,6.7 .8-tetrahydro- 1, 81 naihthvri din- 2-vl )-nronvfl-tetrahydro-nvrimi din- 1 -vl -propioni c acid (4-13) To a solution of 4-12 (0.20 g, 0.41 mmol) in EtOH (5 naL) was added 1N NaOH (0.5 ml, 0.5 mnmol). After stirring for 2 h, the solvents were evaporated and the residue was cbromatographed (silica gel, 25:10:1:1 followed by 15:10:1:1 ethyl acetate /EtOH /water /NIH4OH) to give 4-13 as a white solid.

TLC Rf 0.13 (10:10:1:1 ethyl acetate/EtOH/water/NH4OH).

1 H NMR (300 MiHz, CD3OD) 8 7.44 1H, J=7 Hz), 7.16 1Hi, J=7 Hz), 6.76 (d 1H, J=7 Hz), 6.65 1H), 5.97 1H, J=7 Hz), 6.06 (in, 1H), 4.52 (t, 2H, J= 9 Hz), 3.95 (mn, 1H), 3.46 (mn, 2H), 3.38 (in, Ill), 3.18 (in, 3H), 2.75 (mn, 8H), 1.91 (in, 6H), 1.76 (in, 2H).

-86- WO 99/30713 PTU9/68 PCTIUS98/26485 SCHEME A Synthesis of RadioliL-and for SPA Assay

H

2 NY. ~C0 2

H

0HNH 2 A-1 So 2 c I NaOH, dioxane

H

2 0 A-2 1. Br 2 7 NaOH,

H

2 0 2. HCI -87- WO 99/30713 WO 9930713PCT[US98/26485 SCHEME A. cont'd.

IHCI

EtOH HCI* H 2 N "<C02C H 2

CH

3 A-4

/CO

2

CH

2

CH

3

\N

H

2 N

H

2 Pd /C EtOH :020 H 2

CH

3 6N HOI -88- WO 99/30713 WO 9930713PCTIUS98/26485 SCHEME A, cont'd

HCI*H

2 NfN) A-6

HCIH

2 N C0 2 2

H

H HNSO 2

C

6

H

4

I

EDO, HOBT, NMM, DMF

H

2

CH

3 A-7 6N HOI 6 00 C A-8 0 -89- WO 99/30713 WO 9930713PCT/LUS98/26485

(CH

3 Sn) 2 Pd(PPh 3 4 dioxane, 900 C Sn(C H 3 3 C0 2

H

0-1 N-(4Jod-DhevlslfonlamnoL9-asaa~n A c-odo ah AIfter 2.0 h, the rea ixture Asocetaed)h reiu was g 7. m) disod in n H20 (3 0 ml) and then washe wtEtac.e The aqueous portion was cooled to 0 0 C and then acidified with concentrated HCl. The solid was collected and then washed with Et2O to provide acid A-2 as a white solid.

IH NMR (300 MHz, D20) 6 7.86 2H, J=8Hz 7.48 2H, J=8Hz) 3.70 (in, 1H), 2.39 2H).

2(S)-(4-Iodo-phenvlsulfonvl amino)-D-alanine (A-3) To a stirred solution of NaOH (7.14 g, 181.8 mirnol) and ml) at 0 0 C was added Br2 (1.30 ml, 24.9 mmiol) dropwise over a ten WO 99/30713 PCT/US98/26485 minute period. After -5 minutes, acid A-2 (9.9 g, 24.9 mmol), NaOH (2.00 g, 49.8 mmol) and H20 (35 ml) were combined, cooled to 0°C and then added in a single portion to the reaction. After stirring for minutes at 0°C, the reaction was heated to 90 0 C for 30 minutes and then recooled to 0°C. The pH was adjusted to -7 by dropwise addition of concentrated HC1. The solid was collected, washed with EtOAc, and then dried in vacuo to provide acid A-3 as a white solid.

1 H NMR (300 MHz, D20) 6 8.02 2H, J=8Hz), 7.63 2H, J=8Hz), 4.36 1H), 3.51 (dd, 1H, J=5Hz, 13Hz) 3.21 1H).

Ethyl 2(S)-(4-iodo-phenvlsulfonvlamino)-3-alanine-hydrochloride (A-4) HC1 gas was rapidly bubbled through a suspension of acid A-3 (4.0 g, 10.81-mmol) in EtOH (50 ml) at 0 C for 10 minutes. The cooling bath was removed and the reaction was heated to 60GC. After 18 h, the reaction was concentrated to provide ester A-4 as a white solid.

1 H NMR (300 MHz, CD30D) 5 7.98 2H, J=8Hz), 7.63 2H, J=8Hz), 4.25 1H, J=5Hz), 3.92 2H), 3.33 1H), 3.06 1H), 1.01 3H, J=7Hz).

Ethyl 4-r2-(2-AminoDvridin-6-vl)ethyllbenzoate A mixture of ester A-5 (700 mg, 2.63 mmol), (for preparation, see: Scheme 29 of PCT International Application Publication No. WO 95/32710, published December 7, 1995) 10% Pd/C (350 mg) and EtOH were stirred under 1 atm H2. After 20 h, the reaction was filtered through a celite pad and then concentrated to provide ester as a brown oil.

TLC Rf 0.23 (silica, 40% EtOAc/hexanes) 1 H NMR (300 MHz, CDC13) 5 7.95 2H, J=8Hz), 7.26 3H), 6.43 (d, 1H, J=7Hz), 6.35 1H, J=8Hz), 4.37 4H), 3.05 2H), 2.91 2H), 1.39 3H, J=7Hz).

4-f2-(2-Aminovpridin-6-vl)ethvllbenzoic acid hydrochloride (A-6) A suspension of ester A-5a (625 mg, 2.31 mmol) in 6N HC1 (12 ml) was heated to 60C. After -20 h, the reaction was concentrated to give acid A-6 as a tan solid.

-91- WO 99/307 13 PTU9/68 PCTIUS98/26485 1 H NM7R (300 MHz, CD3OD) 6 7.96 2H, J=8Hz), 7.80 (in, 7.33 (d, 2H, J=8Hz), 6.84 1H, J=9Hz), 6.69 1H, J=7Hz), 3.09 (mn, 4H).

Ethyl 4-[2-(2-Aminopyridin-6-yl)ethyllbenzoyl-2(S)-(4-iodoph enyl sulfonyl amino)- D-al anine (A-7) A solution of acid 15- (400 mng, 1.43 inmol), amine A-4 (686 ing, 1.57 mmol), EDC (358 ing, 1.86 rniol), HOET (252 ing, 1.86 mmol), NIMM (632 p.1, 5.72 inmol) in DMF (10 ml) was stirred for -20 h.

The reaction was diluted with EtOAc and then washed with sat.

NaHCO3, brine, dried (MgSO4) and concentrated. Flash chromatography (silica, EtOAc then 5% isopropanol/EtOAc) provided amnide A-7 as a white solid.

TLC Rf 0.4 (silica, 10% isopropanol/EtOAc) 1 H NMR (300 MHz, CD3OD) 5 7.79 2H, J=9Hz) 7.61 2H, J=8Hz), 7.52 2H, J=9Hz), 7.29 (mn, 1H), 7.27 2H, J=8Hz), 4.20 (in, 1H), 3.95 2H, J=7Hz), 3.66 (dd, 1H, J=6Hz, 14Hz), 3.49 (dd, 1H, J=8Hz, 13Hz), 3.01 (in, 2H), 2.86 (mn, 2H), 1.08 3H, J=7Hz).

4-[2-(2-Aminopyridin-6-yl)ethyllbenzoyl-2(S)-(4-iodophenylsulfonylainino)-f3-alanine (A-8) A solution of ester A-7 (200 mng, 0.32 13 mmol) and 6N HCl ml) was heated to 60*C. After -20 h, the reaction mixture was concentrated. Flash chromatography (silica, 20:20:1:1 EtOAcfEtOHI iNH40H/H20) provided acid A-8 as a white solid.

TLC Rf 0.45 (silica, 20:20:1:1 EtOAc/EtOH/NI{40H1H20) 1 H NMR (400 MHz, DMSO) 5 8.40 (in, 1H1), 8.14 (Bs, 1H), 7.81 2H, J=8Hz), 7.62 2H, J=8Hz), 7.48 2H, J=8Hz), 7.27 (mn, 3H), 6.34 1H, J=7Hz), 6.25 1H, J=8Hz), 5.85 (bs, 2H), 3.89 (bs, 1H), 3.35 (mn, 2H), 2.97 (mn, 2H), 2.79 (in, 2H).

4-2(-mnprdn6y~ty~ezy-()(-rmtysanl phenyl sulfonvl amino4--alanine A solution of iodide A-8 (70 ing, 0.1178 mmol), [(CH3)3Sn12 (49 0.2356 mmol), Pd(PIPh3)4 (5 mg) and dioxane (7 ml) was heated to -92- WO 99/30713 PCTIUS98/26485 0 C. After 2 h, the reaction was concentrated and then purified by preparative HPLC (Delta-Pak C18 15 piM 100A°, 40 x 100 mm; 95:5 then 5:95 H20/CH3CN) to provide the trifluoroacetate salt. The salt was suspended in H20 (10 ml), treated with NH40H (5 drops) and then lyophilized to provide amide A-9 as a white solid.

1H NMR (400 MHz, DMSO) 5 8.40 1H), 8.18 1H, J=8Hz), 7.67 (m, 7.56 2H, J=8Hz), 7.29 2H, J=8Hz), 6.95-7.52 2H), 6.45 (bs, 2H), 4.00 1H), 3.50 1H), 3.33 1H), 2.97 2H), 2.86 2H).

4-[2-(2-Aminopyridin-6-yl)ethyl]benzoyl-2(S)-4- 1 2 5 iodophenvlsulfonvlamino- -alanine An iodobead (Pierce) was added to a shipping vial of 5 mCi of Na 1 2 5 I (Amersham, IMS30) and stirred for five minutes at room temperature. A solution of 0.1 mg of A-9 in 0.05 mL of 10% H2SO4/MeOH was made and immediately added to the Nal 2 5 I/iodobead vial. After stirring for three minutes at room temperature, approximately 0.04-0.05 mL of NH40H was added so the reaction mixture was at pH 6-7. The entire reaction mixture was injected onto the HPLC for purification [Vydac peptide-protein C-18 column, 4.6 x 250 mm, linear gradient of 10% acetonitrile (TFA):H20 TFA) to 90% acetonitrile (0.1% TFA) over 30 minutes, 1 mL/min]. The retention time of A-10 is 17 minutes under these conditions. Fractions containing the majority of the radioactivity were pooled, lyophilized and diluted with ethanol to give approximately 1 mCi of A-10, which coeluted on HPLC analysis with an authentic sample of A-8.

Instrumentation: Analytical and preparative HPLC was carried out using a Waters 600E Powerline Multi Solvent Delivery System with 0.1 mL heads with a Rheodyne 7125 injector and a Waters 990 Photodiode Array Detector with a Gilson FC203 Microfraction collector. For analytical and preparative HPLC, a Vydac peptide-protein C-18 column, 4.6 x 250 mm was used with a C-18 Brownlee modular guard column. The acetonitrile used for the HPLC analyses was Fisher Optima grade. The HPLC radiodetector used was a Beckman 170 Radioisotope detector. A Vydac C-18 protein and peptide column, 3.9 x -93- WO 99/30713 PCT/US98/26485 250 mm was used for analytical and preparative HPLC. Solutions of radioactivity were concentrated using a Speedvac vacuum centrifuge.

Calibration curves and chemical concentrations were determined using a Hewlett Packard Model 8452A UV/Vis Diode Array Spectrophotometer.

Sample radioactivities were determined in a Packard A5530 gamma counter.

The test procedures employed to measure cvp3 and binding and the bone resorption inhibiting activity of the compounds of the present invention are described below.

BONE RESORPTION-PIT ASSAY When osteoclasts engage in bone resorption, they can cause the formation df-pits in the surface of bone that they are acting upon.

Therefore, when testing compounds for their ability to inhibit osteoclasts, it is useful to measure the ability of osteoclasts to excavate these resorption pits when the inhibiting compound is present.

Consecutive 200 micron thick cross sections from a 6 mm cylinder of bovine femur diaphysis are cut with a low speed diamond saw (Isomet, Beuler, Ltd., Lake Bluff, Il). Bone slices are pooled, placed in a 10% ethanol solution and refrigerated until further use.

Prior to experimentation, bovine bone slices are ultrasonicated twice, 20 minutes each in H20. Cleaned slices are placed in 96 well plates such that two control lanes and one lane for each drug dosage are available. Each lane represents either triplicate or quadruplicate cultures. The bone slices in 96 well plates are sterilized by UV irradiation. Prior to incubation with osteoclasts, the bone slices are hydrated by the addition of 0.1 ml aMEM, pH 6.9 containing 5% fetal bovine serum and 1% penicillin/streptomycin.

Long bones from 7-14 day old rabbits (New Zealand White Hare) are dissected, cleaned of soft tissue and placed in aMEM containing 20 mM HEPES. The bones are minced using scissors until the pieces are <1 mm and transferred to a 50 ml tube in a volume of ml. The tube is rocked gently by hand for 60 cycles, the tissue is sedimented for 1 min., and the supernatant is removed. Another 25 ml of medium is added to the tissue and rocked again. The second -94- WO 99/30713 PCT/US98/26485 supernatant is combined with the first. The number of cells is counted excluding erythrocytes (typically 2 x 107 cells/ml). A cell suspension consisting of 5 x 106/ml in aMEM containing 5% fetal bovine serum, nM 1,25(OH)2D3, and pencillin-streptomycin is prepared. 200 ml aliquots are added to bovine bone slices (200 mm x 6 mm) and incubated for 2 hrs. at 37°C in a humidified 5% CO, atmosphere. The medium is removed gently with a micropipettor and fresh medium containing test compounds is added. The cultures are incubated for 48 hrs., and assayed for c-telopeptide (fragments of the al chain of type I collagen) by Crosslaps for culture media (Herlev, Denmark).

Bovine bone slices are exposed to osteoclasts for 20-24 hrs and are processed for staining. Tissue culture media is removed from each bone slice: -Each well is washed with 200 ml of H20, and the bone slices are then fixed for 20 minutes in 2.5% glutaraldehyde, 0.1 M cacodylate, pH 7.4. After fixation, any remaining cellular debris is removed by 2 min. ultrasonication in the presence of 0.25 M followed by 2 X 15 min ultrasonication in H20. The bone slices are immediately stained for 6-8 min with filtered 1% toluidine blue and 1% borax.

After the bone slices have dried, resorption pits are counted in test and control slices. Resorption pits are viewed in a Microphot Fx (Nikon) fluorescence microscope using a polarizing Nikon IGS filter cube. Test dosage results are compared with controls and resulting values are determined for each compound tested.

The appropriateness of extrapolating data from this assay to mammalian (including human) disease states is supported by the teaching found in Sato, t al., Journal of Bone and Mineral Research, Vol. 5, No. 1, pp.31-40, 1990, which is incorporated by reference herein in its entirety. This article teaches that certain bisphosphonates have been used clinically and appear to be effective in the treatment of Paget's disease, hypercalcemia of malignancy, osteolytic lesions produced by bone metastases, and bone loss due to immobilization or sex hormone deficiency. These same bisphosphonates are then tested in the resorption pit assay described above to confirm a WO 99/30713 PCT/US98/26485 correlation between their known utility and positive performance in the assay.

EIB ASSAY Duong et al., J. Bone Miner. Res., 8: S378 (1993) describes a system for expressing the human integrin av33. It has been suggested that the integrin stimulates attachment of osteoclasts to bone matrix, since antibodies against the integrin, or RGD-containing molecules, such as echistatin (European Publication 382 451), can effectively block bone resorption.

Reaction Mixture: 1. 175 pl TBS buffer (50 mM Tris *HC1 pH 7.2, 150 mM NaC1, 1% BSA, 1 mM CaC12, 1 mM MgCl2).

2. 25 pl cell extract (dilute with 100 mM octylglucoside buffer to give 2000 cpm/25 1l).

3. 1 2 5 I-echistatin (25 pl/50,000 cpm) (see EP 382 451).

4. 25 al buffer (total binding) or unlabeled echistatin (nonspecific binding).

The reaction mixture was then incubated for 1 h at room temp. The unbound and the bound av33 were separated by filtration using a Skatron Cell Harvester. The filters (prewet in 1.5% polyethyleneimine for 10 mins) were then washed with the wash buffer mM Tris HC1, 1mM CaC12/MgC12, pH The filter was then counted in a gamma counter.

SPA ASSAY

MATERIALS:

1. Wheat germ agglutinin Scintillation Proximity Beads (SPA): Amersham 2. Octylglucopyranoside: Calbiochem 3. HEPES: Calbiochem -96- WO 99/30713 PCT/US98/26485 4. NaCI: Fisher CaCl2: Fisher 6. MgC12: SIGMA 7. Phenylmethylsulfonylfluoride (PMSF): SIGMA 8. Optiplate: PACKARD 9. Compound A-10 (specific activity 500-1000 Ci/mmole) test compound 11. Purified integrin receptor: av33 was purified from 293 cells overexpressing avP3 (Duong et al., J. Bone Min. Res., 8:S378, 1993) according to Pytela (Methods in Enzymology, 144:475, 1987) 12. Binding buffer: 50 mM HEPES, pH 7.8, 100 mM NaC1, 1 mM Ca 2 0.5 mM PMSF 13. 50 mM octylglucoside in binding buffer: 50-OG buffer

PROCEDURE:

1. Pretreatment of SPA beads: 500 mg oflyophilized SPA beads were first washed four times with 200 ml of 50-OG buffer and once with 100 ml of binding buffer, and then resuspended in 12.5 ml of binding buffer.

2. Preparation of SPA beads and receptor mixture In each assay tube, 2.5 p1 (40 mg/ml) of pretreated beads were suspended in 97.5 [il of binding buffer and 20 p.l of buffer. 5 p1 (-30 ng/pl) of purified receptor was added to the beads in suspension with stirring at room temperature for minutes. The mixture was then centrifuged at 2,500 rpm in a Beckman GPR Benchtop centrifuge for 10 minutes at 4 0 C. The pellets were then resuspended in 50 pl of binding buffer and pl of 50-OG buffer.

-97- WO 99/30713 PCT/US98/26485 3. Reaction The following were sequentially added into Optiplate in corresponding wells: Receptor/beads mixture (75 ml) (ii) 25 pl of each of the following: compound to be tested, binding buffer for total binding or A-8 for non-specific binding (final concentration 1 jiM) (iii) A-10 in binding buffer (25 final concentration 40 pM) (iv) Binding buffer (125 g1) Each plate was sealed with plate sealer from PACKARD and incubated overnight with rocking at 4°C 4. Plates were counted using PACKARD TOPCOUNT inhibition was calculated as follows: A total counts B nonspecific counts C sample counts inhibition x 100 OCFORM ASSAY Osteoblast-like cells (1.8 cells), originally derived from mouse calvaria, were plated in CORNING 24 well tissue culture plates in aMEM medium containing ribo- and deoxyribonucleosides, 10% fetal bovine serum and penicillin-streptomycin. Cells were seeded at 40,000/well in the morning. In the afternoon, bone marrow cells were prepared from six week old male Balb/C mice as follows: Mice were sacrificed, tibiae removed and placed in the above medium. The ends were cut off and the marrow was flushed out of the cavity into a tube with a 1 mL syringe with a 27.5 gauge needle. The marrow was suspended by pipetting up and down. The suspension was passed through >100 pm nylon cell strainer. The resulting suspension was centrifuged at 350 x g for seven minutes. The pellet was -98- WO 99/30713 PCT/US98/26485 resuspended, and a sample was diluted in 2% acetic acid to lyse the red cells. The remaining cells were counted in a hemacytometer. The cells were pelleted and resuspended at 1 x 106 cells/mL. 50 (JL was added to each well of 1.8 cells to yield 50,000 cells/well and 1,25-dihydroxy-vitamin D3 (D3) was added to each well to a final concentration of 10 nM. The cultures were incubated at 37 0 C in a humidified, 5% C02 atmosphere.

After 48 h, the medium was changed. 72 h after the addition of bone marrow, test compounds were added with fresh medium containing D3 to quadruplicate wells. Compounds were added again after 48 h with fresh medium containing D3. After an additional 48 the medium was removed, cells were fixed with 10% formaldehyde in phosphatebuffered saline for 10 minutes at room temperature, followed by a 1-2 minute treatment with ethanol:acetone and air dried. The cells were then stained for tartrate resistant acid phosphatase as follows: The cells were stained for 10-15 minutes at room temperature with 50 mM acetate buffer, pH 5.0 containing 30 mM sodium tartrate, 0.3 mg/mL Fast Red Violet LB Salt and 0.1 mg/mL Naphthol AS -MX phosphate. After staining, the plates were washed extensively with deionized water and air dried. The number of multinucleated, positive staining cells was counted in each well.

ATTACHMENT ASSAY Duong et al., J. Bone Miner. Res., 11: S290 (1996), describes a system for expressing the human (av35 integrin receptor.

Materials: 1. Media and solutions used in this assay are purchased from BRL/Gibco, except BSA and the chemicals are from Sigma.

2. Attachment medium: HBSS with 1 mg/ml heat-inactivated fatty acid free BSA and 2 mM CaC12.

3. Glucosaminidase substrate solution: 3.75 mM p-nitrophenyl N-acetyl-beta-D-glucosaminide, 0.1 M sodium citrate, 0.25% Triton, pH -99- WO 99/30713 PCT/US98/26485 4. Glycine-EDTA developing solution: 50 mM glycine, 5 mM EDTA, pH 10.5.

Methods: 1. Plates (96 well, Nunc Maxi Sorp) were coated overnight at 4°C with human vitronectin (3 ug/ml) in 50 mM carbonate buffer (pH using 100 p.l/well. Plates were then washed 2X with DPBS and blocked with 2% BSA in DPBS for 2h at room temperature. After additional washes (2X) with DPBS, plates were used for cell attachment assay.

2. 293 (avp5) cells were grown in MEM media in presence of fetal calf serum to 90% confluence. Cells were then lifted from dishes with 1X Trypsin/EDTA and washed 3X with serum free MEM. Cells were resuspended in attachment medium (3 X 105 cells/mi).

3. Test compounds were prepared as a series of dilutions at 2X concentrations and added as 50 l/well. Cell suspension was then added as 50 pl/well. Plates were incubated at 37 0

C

with 55 C02 for 1 hour to allow attachment.

4. Non-adherent cells were removed by gently washing the plates (3X) with DPBS and then incubated with glucosaminidase substrate solution (100 pl/well), overnight at room temperature in the dark. To quantitate cell numbers, standard curve of glucosaminidase activity was determined for each experiment by adding samples of cell suspension directly to wells containing the enzyme substrate solution.

The next day, the reaction was developed by addition of 185 pl/well of glycine/EDTA solution and reading absorbance at 405 nm using a Molecular Devices V-Max plate reader.

Average test absorbance values (4 wells per test samples) were calculated. Then, the number of attached cells at each drug concentration was quantitated versus the standard curve of cells using the Softmax program.

-100- WO 99/30713 PCT/US98/26485 EXAMPLE OF A PHARMACEUTICAL FORMULATION As a specific embodiment of an oral composition, 100 mg of a compound of the present invention are formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.

Representative compounds of the present invention were tested and found to bind to human av33 integrin. These compounds are generally found to have IC50 values less than about 100 nM in the SPA assay.

Representative compounds of the present invention were tested and generally found to inhibit 50% the attachment of expressing cells-to plates coated with vitronectin at concentrations of about 1 pM.

While the invention has been described and illustrated in reference to certain preferred embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, effective dosages other than the preferred doses as set forth hereinabove may be applicable as a consequence of variations in the responsiveness of the mammal being treated for severity of bone disorders caused by resorption, or for other indications for the compounds of the invention indicated above. Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be limited only by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

-101-

Claims (31)

1. A compound of the formula R6 W-X-Y-Z C0 2 R 9 R 8 wherein W is selected from the group consisting of RNi N N NN N II IN 5 N H H Ny N N ON Xis -(CH 2 wherein any methylene (CH 2 carbon atom is either unsubstituted or substituted with one or two RI substituents; Y is selected from the group consisting of -(CH 2 )m-NR4-(CH 2 -~(CH 2 )mSO-(CH 2 -(CH2)mSO 2 -(0H 2 -(CH 2 )m0O(CH 2 )n0O(CH 2 2 )n-NR 4 -(CH 2 -(0H 2 )m-NR 4 -(CH 2 )n-NR 4 -(CH 2 -(CH2)m0O(CH2)nS(CH2)p-, -(CH2)mS(CH2)n-S(CH2)p-, -(CH2)mNR 4 (CH2)nS(CH2)p-, -(CH2)mNR 4 (CH2)n0O(CH2)p-, -(CH2)mS(CH2)n0O(CH2)p-, and -(CH2)m-S-(CH 2 )n-NR 4 -(CH 2 wherein any methylene (CH 2 carbon atom in Y, other than in R 4 can be substituted by one or two R 3 substituents; ~AL~Z Zis I B AA ]08974 doc: sak 0 HN/ N 4N IN o 0 0 N i l N o ,and 0 R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, 01.10 alkyl, C3-8 cycloalkyl, 5: 5 C 3 8 cycloheteroalkyl, C3-8 cycloalkyl 01.6 alkyl, C 3 -8 cycloheteroalkyl Ci-6 alkyl, aryl, aryl 01-8 alkyl, amino, *amino Ci-8 alkyl, C1-3 acylamino, 01-3 acylamino 01-8 alkyl, S (Ci-6 alkyI)pamino, (Ci-6 alkyl)pamino 01-8 alkyl, aCi-4 alkoxy, Oi-4 alkoxy Ci-6 alkyl, hydroxycarbonyl, to*: 10 hydroxycarbonyl Ci-6 alkyl, 01-3 alkoxycarbonyl, C1-3 alkoxycarbonyl Ci-6 alkyl, hydroxycarbonyl- 1-6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, Ci-6 alkyloxy- 01-6 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, Ci-8 alkyl-S(O)p, (Oi-8 alkyl)paminocarbonyl, 15 C1-8 alkyioxycarbonylamlno, aIky)paminocarbonyloxy, S (aryl Ci-8 alkyl)pamino, (aryl)pamino, aryl Oi-8 alkylsulfonylamino, and C1-8 alkylsulfonylamino; or two R 1 substituents, when on the same carbon atom, are taken together with the carbon atom to which they are attached to form a carbonyl group; each R 3 is independently selected from the group consisting of hydrogen, aryl, Ci-io alkyl, aryl-(0H 2 )rSO-(H 2 aryl-(CH2)rO(O)-(H 2 aryl-(CH2)r-C(O)N)-(CH 2 AL, aryl-(0H 2 )rN(R 4 2 [R:\LIBAA]08974.doc:sak 104 aryl-(CH2)rN(R 4 halogen, hydroxyl, oxo' trifluoromethyl, C,-8 al kylcarbon yl amino, aryl C1-5 alkoxy, alkoxycarbonyl, (01.8 alkyl)paminocarbonyl, C 16 alkylcarbonyloxy, C 3 -8 cycloalkyl, (01.8 aikyI)pamino, amino 01.8 alkyl, arylamninocarbonyl, aryl 01.5 alkylamninocarbonyl, amninocarbonyl, amninocarbonyl C1- alkyl, hydroxycarbonyl, hydroxycarbonyl 01.8 alkyl, HC=-C-(CH 2

03-7 cycloalkyl-C-=C-(CH2)t-, aryI-C=-C-(C H2)t-, Ci-6 alkylaryI-C=-C-(CH2)t-, 0H2=CH-(CH2)t-, Ci- alkyi-CH=CH-(CH2)t-, 03.7 cycloalkyl-CH=CH-(0H2)t-, aryl-CH=CH-(0H 2 C1- alkylaryl-CH=CH-(CH2)t-, C1-6 alkyl-S02-(CH2)t-, C1- alkylaryl-SO2-(CH2)t-, C1- alkoxy, aryl Ci-6 alkoxy, aryl 01-6 alkyl, (01.8 alkyl)pamino 01.8 alkyl, [R\L I BAA] 08974.doc: sak 105 (aryI)pamino, (aryi)pamino C1- alkyl, (aryl 0 i- alkyI)pamino, (aryl C 1 alkyI)pamino C1- alkyl, arylcarbonyloxy, aryl 01-6 alkylcarbonyloxy, (Cl 16 alkyl)paminocarbonyloxy, Cl1 alkylsuylfonylamino, arylsu Ifonylamino, 0148 alkylsulfonylamino 016 alkyl, arylsulfonylamino 01-6 alkyl, aryl 01-6 alkylsulfonylamino, aryl C1.6 alkylsulfonylamino 01-6 alkyl, Cl8alkoxycarbonylamino, Cli alkoxycarbonylamino C1- alkyl, aryloxycarbonylamino Cio8 alkyl, aryl Ci- alkoxycarbonylamino, aryl 0148 alkoxycarbonylamino 0148 alkyl, 014 alkylcarbonylamino, C018 alkylcarbonylamino 01-6 alkyl, *arylcarbonylamino Oi- alkyl, aryl 01-6 alkylcarbonylamino, aryl 01-6 alkylcarbonylamino 01-6 alkyl, aminocarbonylamino 01- alkyl, (01- aikyI)paminocarbonylamino, (01-8 alkyI)paminocarbonylamino Cl1 alkyl, (aryl)paminocarbonylamino 01-6 alkyl, (aryl 0148 alkyI)paminocarbonylamino, (aryl Ci- alkyl)paminocarbonylamino 01-6 alkyl, aminosuifonylamino 01-6 alkyl, (0148 alkyl)paminosuifonylamino, (0148 alkyl)paminosulfonylamino 0146 alkyl, (aryl) paminosulfonylamino 0146 alkyl, (aryl Oi- alkyl) paminosulfonylamino, 3 5O (aryl C1-8 alkyl) paminosulfonylamino 0i- alkyl, [RALI BAA]08974.doc: sak 106 C1-6 alkylsulfonyl, C1-6 alkylsulfonyl C1-6 alkyl, arylsulfonyl Ci.6 alkyl, aryl Ci- alkylsulfonyl, aryl C 1 -6 alkylsulfonyl C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkylcarbonyl Ci-6 alkyl, arylcarbonyl Cv-6 alkyl, aryl C 1 -6 alkylcarbonyl, aryl C1-6 alkylcarbonyl Ci-6 alkyl, C1- .tioabnyaio K:C 16 alkylthiocarbonylaminoC- akl arylthiocarbonylamino Ci-6 alkyl, aryl C 1 -6 alkylthiocarbonylamino, aryl Ci-6alkylthiocarbonylamino Ci-6 alkyl, (Ci-8 alkyI)paminocarbonyl C 1 -6 alkyl, (aryl)paminocarbonyl C1-6 alkyl, (aryl Ci-8 alkyl)paminocarbonyl, and (aryl Ci-8alkyl)paminocarbonyl C1-6 alkyl; ortwo R3substituents, when on the same carbon atom are taken together with the carbon atom to which they are attached to form a carbonyl group or a cyclopropyl group, wherein any of the alkyl groups of R 3 are either unsubstituted or substituted with one to three R 1 substituents, and provided that each R 3 is selected such that in the resultant compound the carbon atom or atoms to which R 3 is attached is itself attached to no more than one heteroatom; each R 4 is independently selected from the group consisting of hydrogen, aryl, aminocarbonyl, C 3 -8 cycloalkyl, amino C 1 -6 alkyl, (aryl)paminocarbonyl, (aryl CI.5 alkyl)paminocarbonyl, hydroxycarbonyl Ci-6 alkyl, CI-8 alkyl, aryl C1-6 alkyl, RAL IBAA108 974.doc: sak 107 (0i- alkyl)pamino C 2 -6 alkyl, (aryl 0i- alkyl)pamino C26 alkyl, C1-8 alkylsulfonyl, CI-a alkoxycarbonyl, arylxycarbonyl, aryl C1- alkoxycarbonyl, 01-8 alkylcarbonyl, arylarbonyl, aryl C1- alkylcarbonyl, (Ci- alkyl)paminocarbonyl, aminosulfonyl, 01-8 alkylaminosulfonyl, (aryi)paminosulfonyi, (aryl C1-8 alkyl)paminosulfonyl, arylsulfonyl, aryl C1- alkylsulfonyl, C1-6 alkylthiocarbonyl, aryithiocarbonyl, and aryl C1- alkyithiocarbonyl, wherein any of the alkyl groups of R 4 are either unsubstituted or substituted with one to three R 1 substituents; R 5 and R 6 are each independently selected from the group consisting of hydrogen, Clio alkyl, aryl, 2 2 aryl-(CH2)rC(O)-(CH 2 aryl-(CH2)r-C(O)-N (R 4 )-(CH 2 aryl-(CH2)r-N(R 4 2 aryl-(CH2),-N(R 4 )-(CH 2 halogen, A hydroxyl, 01- alkylcarbonylamino, k 1 aryl C15 alkoxy, [R:\LIBAA]08974.doc:sak 01-5 alkoxycarbonyl, (Oi-8 alkyl)paminocarbonyl, 01-6 alkylcarbonyloxy, C3- cycloalkyl,. (Ci- alkyI)pamino, amino 01-6 alkyl, arylamninocarbonyl, aryl Cl.5 alkylamninocarbonyl, amninocarbonyl, amninocarbonyl alkyl, hydroxycarbonyl, hydroxycarbonyl Ci- alkyl, HC-=C-(CH 2 *Ci- alkyI-C-=C-(CH2)r-, 03-7 cycloalkyI-C=-C-(CH 2 aryI-C=-C-(CH2)t-, 01.6 alkylaryI-C 0H2=CH-(0H2)t-, 01.6 alkyl-CH=CH-(0H 2 037 cycloalkyl-CH=CH-(CH 2 aryI-CH=CH-(CH2)t-, 01.6 alkylaryI-0H=0H-(0H2)t-, 01.6 alkyl-S0 2 -(CH 2 01.6 alkylaryl-S02-(CH2)t-, 01.6 alkoxy, aryl 01-6 alkoxy, aryl 01.6 alkyl, (01.6 alkyI)pamino 01-6 alkyl, (aryI)pamino, (aryl)pamino C1-6 alkyl, (aryl 01-6 alkyI)pamnino, (aryl C1-6 aikyl)pamino 01-6 alkyl, arylcarbonyloxy, Aaryl 01.6 alkylcarbonyloxy, (01.6 alkyl)paminocarbonyloxy, [R:\LIBAA]08974.doc:sak 109 0 i-8 alkylsuylfonylamino, a ryIsu If onylamino, 0 i-8 alkylsulfonylamino 01.6 alkyl, arylsulfonylamino CI-6 alkyl, aryl 01.6 alkylsulfonylamino, aryl 01.6 alkylsulfonylamino Cl-6 alkyl, C 18 alkoxycarbonylamino, 0148 alkoxycarbonylamino 0148 alkyl, aryloxycarbonylamino 0148 alkyl, 0 aryl 0i- alkoxycarbonylamino, aryl Oi-8 alkoxycarbonylamino 0148 alkyl, 01-8 alkylcarbonylamino, 0148 alkylcarbonylamino 01.6 alkyl, arylcarbonylamino 01.6 alkyl, aryl 01.6 alkylcarbonylamino, aryl 01.6 alkylcarbonylamino 01-6 alkyl, aminocarbonylamino 01.6 alkyl, (01-8 alkyl)paminocarbonylamino, (0148 alkyl)paminocarbonylamino Oi6 alkyl, (aryl)paminocarbonylamino 01-6 alkyl, :(aryl 0148 alkyl)paminocarbonylamino, *(aryl 0148 alkyl)paminocarbonylamino Ci- alkyl, aminosulfonmylamino Ci. alkyl, (0148 alkyI)paminosulfonylamino, (0148 alkyI)paminosulfonylamino 0 i- alkyl, (aryl)paminosulfonylamino 01.6 alkyl, (aryl C0- alkyl)paminosulfonylamino, (aryl 0148 alkyl) paminosulfonylamino 01.6 alkyl, 01.6 alkylsulfonyl, 01.6 alkylsulfonyl Oi.6 alkyl, arylsulfonyl 01.6 alkyl, aryl Cl-6 alkylsulfonyl, aryl Ci-6 alkylsulfonyl 01.6 alkyl, Oi-6 alkylcarbonyl, (1_U Ci-6 alkylcarbonyl 01-6 alkyl, R:\LIBAA108974.doc: sak 110 arylcarbonyl Ci-6 alkyl, aryl C1-6 alkylcarbonyl, aryl Ci-6 alkylcarbonyl Ci-6 alkyl, C1-6 alkylthiocarbonylamino, Cv-6 alkylthiocarbonylamino Ci-6 alkyl, arylthiocarbonylamino C,-6 alkyl, aryl C 16 alkylthiocarbonylamino, aryl Ci-6 alkylthiocarbonylamino C 16 alkyl, (Cl-8 alkyl)paminocarbonyl Ci-6 alkyl, (aryl)paminocarbonyl C1-6 alkyl, (aryl Ci-8 alkyl)paminocarbonyl, and :(aryl C 1 -8 alkyI)paminocarbonyI C 1 -6 alkyl; *or R 5 and R 6 are taken together with the carbon atom to which they are attached to form a carbonyl group, wherein any of the alkyl groups of R 5 and R 6 are either unsubstituted or substituted with one to three R 1 substituents, and provided that each R 5 and R 6 are selected such that in the resultant compound the carbon atom to which R 5 and R 6 are attached is itself attached to no more than one heteroatom; R 7 and R 8 are each independently selected from the group consisting of hydrogen, C1.o alkyl, aryl, aryl-(CH2)rO-(CH 2 aryl-(CH2),C(O)-(CH 2 2 R)-(CH 2 aryl-(CH 2 )rN(R 4 2 aryl-(CH 2 )rN(R 4 2 halogen, hydroxyl, C 1 -8 alkylcarbonylamino, aryl 01-5 alkoxy, alkoxycarbonyl, RAL (0148 alkyl)pam inocarbonyl, 0146 alkylcarbonyloxy, [R:\LIBAA]08974.doc:sak C3- cycloalkyl, (Ci- alkyI)pamino, amino C1- alkyl, arylamninocarbonyl, aryl 01-5 alkylamninocarbonyl, amninocarbonyl, amninocarbonyl C 1 alkyl, hydroxycarbonyl, hydroxycarbonyl Ci- alkyl, Cl16 alkyI-C=-C-(CH 2 **C3-7 cycloalkyI-C=-C-(CH 2 5 aryI-C=-C-(CH 2 isH20CH-(CH2)t-, 01-6 alkyl-CH=CH-(CH2)r, 03-7 cycloalkyI-CH=CH-(CH 2 aryI-CH=CH-(CH2)t-, :Cli. alkyiaryl-CH=CH-(0H 2 01-6 alkyISO2(CH2)t-, 016 aikylaryI-SO2-(CH2)t-, 01-6 alkoxy, aryl Cl- alkoxy, aryl Cl- alkyl, (Ci- alkyI)pamino 0 i- alkyl, (aryl)pamino, (aryl)pamino C,-6 alkyl, (aryl Ci- alkyI)pamino, (aryl C 0 alkyI)pamino 01-6 alkyl, aryicarbonyloxy, aryl Cl- aikylcarbonyloxy, (01-6 alkyI)paminocarbonyloxy, Ovs8 alkylsuylfonylamino, arylcarbonylamino, arylsulfonylamnino, R:LI BAA] 08974.doc: sak Cl- alkylsulfonylamnino 01-6 alkyl, arylsulfonylamino 01-6 alkyl, aryl alkylsulfonylamino, aryl alkylsulfonylamnino C1- alkyl, C1-8 alkoxycarbonylamino, alkoxycarbonylamino alkyl, aryloxycarbonylamnino Ois8 alkyl, aryl C,-8 alkoxycarbonylamnino, aryl C1- alkoxycarbonylamnino CO- alkyl, alkylcarbonylamino, 01-8 alkylcarbonylamino 01-6 alkyl, arylcarbonylamino 01-6 alkyl, 5 ary 01.6 alkylcarbonylamino, aryl 0l- alkylcarbonylamino 01-6 alkyl, amninocarbonylamnino 01-6 alkyl, arylamninocarbonylamino, i (01-8 alkyI)paminocarbonylamino, (01-8 alkyI)paminocarbonylamino 01-6 alkyl, (aryl)paminocarbonylamino 01-6 alkyl, (aryl 01.8 alkyl)paminocarbonylamino, (ay .I8aklpmncroy mn l6akl (aryl 018lfalkylpamino C-alylmn 16akl ayaminosulfonylamino ly, (01-8 alkyl)paminosulfonylaminoC- akl (ary)paminosulfonylamino Oi- alkyl, (aryl CO-8 alkyl)paminosulfonylamino, (aryl C1- alkyl) paminosulfonylamino 01.6 alkyl, 0i- alkylsulfonyl, alkylsulfonyl Oi- alkyl, arylsulfonyl 01-6 alkyl, aryl C1- alkylsulfonyl, aryl CO- alkylsulfonyl C1-6 alkyl, Oi- alkylcarbonyl, r 7 i- alkylarbonyl 0-6 alkyl, ,z 35' arylcarbonyl Oi-6 alkyl, [R:\LIBAA]08974.doc:sak 113 aryi C1-6 alkylcarbonyl, aryl C1-6 alkylcarbonyl 01-6 alkyl, 01-6 alkyithiocarbonylamino, C1-6 alkylthiocarbonylamino C1-6 alkyl, arylthiocarbonylamino 01-6 alkyl, aryl C1-6 alkylthiocarbonylamino, aryl Ci-6 alkyithiocarbonylamino Ci-6 alkyl, (Ci-8 alkyl)paminocarbonyl 0i-6 alkyl, (aryI)paminocarbonyI C1-6 alkyl, (aryl C1-8 alkyI)paminocarbonyI, (aryl C1-8 alkyl)paminocarbonyI Ci-6 alkyl, and

07-20 polycyclyl Co-8 alkylsulfonylamino; wherein any of the alkyl groups of R 7 and R 8 are either unsubstituted or substituted with one to three R 1 substituents, and provided that each R 7 and R 8 are selected such that in the resultant 15i compound the carbon atom to which R 7 and R 8 are attached is itself attached to no more than one heteroatom; R 9 is selected from the group consisting of hydrogen, C1-8 alkyl, aryl, aryl Ci-8 alkyl, 01-8 alkylcarbonyloxy C14 alkyl, aryl Ov-8 alkylcarbonyloxy 014 alkyl, C1-8 alkylaminocarbonylmethylene, and Cl-8dialkylaminocarbonylmethylene; R 1 0 R 1 1 R 12 and R 1 3 are each independently selected from the group consisting of hydrogen, C1-8 alkyl, aryl, halogen, hydroxyl, oxo' aminocarbonyl, C3-8 cycloalkyl, amino 01-6 alkyl, [R:\LIBAA]08974.doc:sak (aryI)paminocarbonyl, hydroxycarbonyl, (aryl 01.5 alkyI)paminocarbony, hydroxycarbonyl Cl- 6 alkyl, aryl Ci- alkyl, (01.6 alkyI)pamino C1-6 alkyl, (aryl 01.6 alkyI)pamino C 2 6 alkyl, Cl-8 alkylsulfonyl, 01.6 alkoxycarbonyl, aryloxycarbonyl, aryl Cl-8 alkoxycarbonyl, Cl-8 alkylcarbonyl, arylcarbonyl, aryl 01.6 alkylcarbonyl, (01.6 alkyI)paminocarbonyl, aminosulfonyl, Cl-8 alkylaminosulfonyl, (aryI)paminosulfonyI, (aryl 01.6 alkyI)paminosulfony, 01-6 alkylsulfonyl, arylsu Ifonyl, *aryl Cl- alkylsulfonyl, aryl Cl- alkylcarbonyl, Cli alkyithiocarbonyl, arylthiocarbonyl, aryl 01.6 alkylthiocarbonyl, aryl-(0H2)r-O-(CH2)s-, aryl-(CH2)rC(O)-(H 2 aryI-(CH2)r-C(O)-N(R 4 )-(CH 2 aryl-(CH2)r-N(R 4 2 aryl-(0H2)r-N(R 4 )-(CH 2 3 03.7 cycloalkyl-C=-C-(CH2)t-, [R:\LIBAA]08974.doc:sak aryI-C=-C-(CH2)t-, 0146 alkylary-C=-C-(CH2)t-, CH2=CH-(0H2)t-, Ci- alkyl-CH=CH-(CH 2 C 37 cycloalkyi-CH=CH-(0H 2 aryI-CH=CH-(CH2)t-, C1.6 alkylaryI-CH=CH-(CH2)r-, 01.6 alkyl-S02-(CH2)t-, Cl-6 alkylaryl-S0 2 -(CH 2 Cl-8 alkylcarbonylamino, aryl 01.5 alkoxy, 01.5 alkoxycarbonyl, (0148 alkyI)paminocarbony, C1. 6 alkyicarbonyloxy, (01.6 alkyl)pamino, aminocarbonyl 01-6 alkyl, 01.6 aikoxy, aryl 01.6 alkoxy, (aryl)pamino, (aryl)pamino 01-6 alkyl, (aryl 01.6 alkyI)pamino, (aryl 01.6 alkyI)pamino 01.6 alkyl, arylcarbonyloxy, aryl 01.6 alkylcarbonyloxy, (01.6 alkyl)paminocarbonyloxy, 0148 alkylsulfonylamino, arylsulfonylamino, 0 1s8 alkylsulfonylamino 01-6 alkyl, arylsulfonylamino Ci-6 alkyl, aryl 01-6 alkylsulfonylamino, aryl C1-6 alkylsulfonylamino 01-6 alkyl, 01.6 alkoxycarbonylamino, Cl-8 alkoxycarbonylamino 0148 alkyl, ~aryloxycarbonylamino 01.6 alkyl, 3 5 /aryl C1-8 alkoxycarbonylamino, [R:\LIBAA]08974.doc:sak aryl 0 i- alkoxycarbonylamino 01-8 alkyl, 01-8 alkylcarbonylamino, Ova8 alkyicarbonylamino Ova6alkyl, aryicarbonylamino C1- alkyl, aryl C1- al kyicarbon yl amino, aryl C1- alkylcarbonylamino Ova6 alkyl, aminocarbonylamino 01-6 alkyl, (01-8 alkyl)paminocarbonylamino (Ova8 alkyI)paminocarbonylamino Ova6 alkyl, (aryl)paminocarbonylamino 01-6 alkyl, (aryl Ova8 alkyi)paminocarbonylamino, *0 (aryl Ova8 alkyl)paminocarbonylamino 01-6 alkyl, *So* aminosulfonmylamino Ova6 alkyl, (01-8 alkyl)paminosulfonylamino, 150 (01-8 alkyl)paminosulfonylamino 01-6 alkyl, (aryI)paminosuifonylamino 01-6 alkyl, *fes: a 0 (aryl C18 alkyl)paminosulfonylamino, (ryl 1-8alkyl)paminosulfonylamino 01-6 alkyl, 01-6 alkylsulfonyl, Oe*9 20 01-6 aikylsulfonyl Ova6 alkyl, arylsulfonyl Ci-6 alkyl, aryl Ova6 alkylsulfonyl, aryl 01-6 alkylsulfonyl 01-6 alkyl, 01.6 alkylcarbonyl, Ova6 aikylcarbonyl 01-6 alkyl, arylcarbonyl C1-6 alkyl, aryl Ova6 alkylcarbonyl, aryl Ova6 alkylcarbonyl C1-6 alkyl, Ova6 alkyithiocarbonylamnino, 0i- alkylthiocarbonylamnino 01-6 alkyl, aryithiocarbonylamnino Ova6 alkyl, aryl i- alkyithiocarbonylamnino, aryl Ova6 alkyithiocarbonylamnino Ova6 alkyl, (Ova8 alkyI)paminocarbonyI Ova6 alkyl, (aryl)paminocarbonyl Ova6 alkyl, R:LI BAA]08974.doc: sak (aryl C1-8 alkyl)paminocarbonyl, and (aryl C1-8 alkyl)paminocarbonyl C1-6 alkyl; wherein any of the alkyl group of R o 1 R 1 1 R 1 2 and R 1 3 are either unsubstituted or substituted with one to three R 1 substituents; wherein each m is independently an integer from 0 to 6; each n is independently an integer from 0 to 6; each p is independently an integer from 0 to 2; each r is independently an integer from 1 to 3; 1o each s is independently an integer from 0 to 3; each t is an integer from 0 to 3; and v is independently an integer from 0 to 6; Sand the pharmaceutically acceptable salts thereof. 2. The compound of claim 1 wherein W is 1 N 15 or H X is -(CH 2 wherein any methylene (CH 2 carbon atom is either unsubstituted or substituted with one or two R 1 substituents; Y is selected from the group consisting of -(CH2)m-, -(CH2)m-0-(CH2)n-, -(CH 2 )m-NR 4 -(CH 2 -(CH 2 )m-S-(CH 2 -(CH 2 )m-SO-(CH 2 -(CH 2 )m-SO2-(CH 2 -(CH2)m-0-H2) 2)n-0-(CH2)p-, -(CH2)m-O-(CH2)n-NR 4 -(CH2)p-, -(CH2)m-NR 4 -(CH2)n-NR 4 and -(CH2)m-NR 4 -(CH2)n-O-(CH2)p-; wherein any methylene (CH 2 carbon atom in Y, other than in R 4 can be substituted by one or two R 3 substituents; and iZ is [R:\LIBAAj08974.doc:sak 118 R 10 Rio H ~i-0 0 or o 3. The compound of claim 2 wherein Y is selected from the group consisting of (CH 2 (CH 2 )m-S-(CH2)n, and (CH 2 )m-NR 4 -(CH 2 )n, wherein any methylene (CH 2 carbon atom in Y, other than in R 4 can be substituted by one or two R 3 substituents; m and n are integers from 0-3; and and v is 0. 4. The compound of claim 3 wherein each R 3 is independently selected from the group consisting of 10 hydrogen, fluoro, trifluoromethyl, aryl, C1-8 alkyl, 15 aryl C 1 -6 alkyl, hydroxyl, oxo, arylaminocarbonyl, aryl C 15 alkylaminocarbonyl, aminocarbonyl, and aminocarbonyl Ci- 1 alkyl; and each R 4 is independently selected from the group consisting of hydrogen, aryl, C 3 -8 cycloalkyl, Ci-8 alkyl, Ci-8 alkylcarbonyl, arylcarbonyl, Ci-6 alkylsulfonyl, arylsulfonyl, aryl Ci-e alkylsulfonyl, aryl Ci-6 alkylcarbonyl, [R:\LIBAA]08974.doc:sak C1-8 alkylaminocarbonyl, aryl 01-5 alkylaminoCarbonyl, aryl C1-8 alkyoxycarbonyl, and C1-8 alkoxycarbonyl. 5. The compound of claim 4 wherein R 6 R 7 and R 8 are each hydrogen and R 5 is selected from the group consisting of hydrogen, aryl, C 14 8 alkyl, aryl-C=-C-(CH2)r-, aryl Ci-6 alkyl, H2=CH-(CH2)r- and HC=-C-(CH 2 The compound of claim 5 wherein R 9 is selected from the group consisting of hydrogen, methyl, and ethyl. 7. The compound of claim 6 wherein R 9 is hydrogen. The compound of claim 4 wherein R 5 R 6 and R 8 are each hydrogen and R 7 is selected from the group consisting of hydrogen, aryl, alkylcarbonylamino, C1-8 alkylsulfonylamino, arylcarbonylamino, arylsu Ifonylamino, C1-8 alkylsulfonylamino C1- alkyl, arylsulfonylamino C1-6 alkyl, aryl C1-6 alkylsulfonylamino, aryl C1-6 alkylsulfonylamino C1-6 alkyl, C1-8 alkoxycarbonylamino, C1-8 alkoxycarbonylamino C1-8s alkyl, aryloxycarbonylamino 0148 alkyl, aryl 0148 alkoxycarbonylamino, aryl 0148 alkoxycarbonylamino 0148 alkyl, 01-8 alkylcarbonylamino C1-6 alkyl, arylcarbonylamino C1-6 alkyl, [R:\LIBAA]08974.doc:sak 120 aryl C1-6 alkylcarbonylamino, aryl C1-6 alkylcarbonylamino 01-6 alkyl, am inocarbon yl amino 01-6 alkyl, (Oi-8 alkyl)paminocarbonylamino, aikyl)paminocarbonylamino 01-6 alkyl, (aryi)paminocarbonyl amino 01-6 alkyl, arylaminocarbonylamino, (aryl C1-8 alkyl)paminocarbonylamino, (aryl C1-8 alkyl)paminocarbonylamino C1-6 alkyl, aminosulfonylamino C1-6 alkyl, .(01-8 alkyl)paminosulfonylamino, (01.6 alkyl)paminosuifonylamino 01.6 alkyl, (aryl)paminosulfonylamino 01.6 alkyl, .(aryi 01-8 alkyI)paminosulfonylamino, (aryl 01.6 alkyl)paminosulfonylamino C1-6 alkyl, 01.6 al kylth iocarbonyl amino, 01-6 alkyltniocarbonylamino 01.6 alkyl, aryithiocarbonylamino 01.6 alkyl, aryl 01-6 alkyithiocarbonylamino, and aryl 01-6 alkylthiocarbonylamino 01-6 alkyl.

9. compound of claim 8 wherein R 7 is selected from the group consisting of hydrogen, aryl, C1-8 alkylcarbonylamino, aryl 01-6 alkylcarbonylamino, arylcarbonylamino, 01-8 alkylsulfonylamino, aryl 01-6 alkylsulfonylamino, arylsu Ifonylamino, 01-8 alkoxycarbonylamino, aryl 01-8 alkoxycarbon yl amino, arylaminocarbonylamino, ?,LI (01.6 alkyI)paminocarbonylamino, (aryl 01.6 alkyl)paminocarbonylamino, LU 335' (01.6 alkyI)paminosulfonylamino, and R\ I BAA ]089 74.doc: sak (aryl C1-8 alkyl)paminosulfonylamino. The compound of claim 9 wherein R 9 is selected from the group consisting of hydrogen, methyl, and ethyl.

11. The compound of claim 10 wherein R 9 is hydrogen.

12. The compound of claim 4 selected from the group consisting of: ethyl 3(S)-(2,3-dihydro-benzofuran-6-yl)-3-{2-oxo-3-[3-(5,6,7,8-tetrahydro-[1 ,8]naphthyridin-2- yl)-propylj-tetrahydro-pyrimidin-1 -yl}-propionate; ethyl 3(S)-(3-fluorophenyl)-3-(2-oxo-3(S or R)-[3-(5,6,7,8-tetrahydro-[1 ,8]naphthyridin-2-yl)- propyl]-piperidin-1 -yl)-propionate; ethyl 3(S)-(3-fluorophenyl)-3-(2-oxo-3(R or S)-[3-(5,6,7,8-tetrahydro-[1 ,8]naphthyridin-2-yl)- :propyl]-piperidin-1 -yl)-propionate; 3(S)-(2,3-dihydro-benzofuran-6-yl)-3-{2-oxo-3[3-(5,6,7,8-tetrahydro-[1 ,8]naphthyridin-2-yl)- propyl]-tetrahydro-pyrimidin-1-yl}-propionic acid; 3(S)-(3-fluorophenyl)-3-(2-oxo-3(S or R)-[3-(5,6,7,8-tetrahydro-[1 ,8]naphthyridin-2-yl)-propyl]- piperidin-1-yl}-propionic acid; 3(S)-(3-fluorophenyl)-3-(2-oxo-3(R or S)-[3-(5,6,7,8-tetrahydro-[1 ,8]naphthyridin-2-y)-propy]- piperidin-1-yl}-propionic acid; and the pharmaceutically acceptable salts thereof. The compound of claim 12 selected from the group consisting of: 20 3(S)-(2,3-dihydro-benzofuran-6-yl)-3-{2-oxo-3-[3-(5,6,7,8-tetrahydro-[1 ,8]naphthyridin-2-yi)- propyl]-tetrahydro-pyrimidin-1-yl}-propionic acid; 3(S)-(3-fluorophenyl)-3-(2-oxo-3(R or ,6,7,8-tetrahydro-[1 ,8]naphthyridin-2-y)-propyl]- piperidin-1-yl)-propionic acid; 3(S)-(3-fluorophenyl)-3-(2-oxo-3(S or R)-[3-(5,6,7,8-tetrahydro-[1 ,8]naphthyridin-2-yl)-propyl]- piperidin-1 -yl)-propionic acid; and the pharmaceutically acceptable salts thereof.

14. A process of preparing an integrin receptor antagonist, the process being substantially as hereinbefore described with reference to any one of the Schemes. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier.

16. A pharmaceutical composition made by combining a compound according to any one of claims i to 13 and a pharmaceutically acceptable carrier. C~RL/~17. A process for making a pharmaceutical composition comprising combining a r7-'Z- compound according to claim 1 and a pharmaceutically acceptable carrier. R:LI BAA]08974.doc: sak 0 0~ 0 0 0 0 0. 0* 00 122

18. A composition of claim 14 which further comprises an active ingredient selected from the group consisting of a) an organic bisphosphonate or a pharmaceutically acceptable salt or ester thereof, b) an estrogen receptor modulator, c) a cytotoxic/antiproliferative agent, d) a matrix metallopropteinase inhibitor, e) an inhibitor of epidermal-derived, fibroblast-derived, or platelet-derived growth factors, f) an inhibitor of VEGF, g) an inhibitor of Flk-1/KDR, Fit-1, Tck/Tie-2, or Tie-1, h) a cathepsin K inhibitor, and i) a prenylation inhibitor, such as a famesyl transferase inhibitor or a geranylgeranyl transferase inhibitor or a dual farnesyl/geranylgeranyl transferase inhibitor; and mixtures thereof.

19. The composition of claim 18 wherein said active ingredient is selected from the group consisting of a) an organic bisphosphonate or a pharmaceutically acceptable salt or ester thereof, b) an estrogen receptor modulator, and c) a cathepsin K inhibitor; and mixtures thereof.

20. The composition of claim 19 wherein said organic bisphosphonate or pharmaceutically acceptable salt or ester thereof is alendronate monosodium trihydrate.

21. The composition of claim 18 wherein said active ingredient is selected from the group consisting of a) a cytotoxic/antiproliferative agent, b) a matrix metallopropteinase inhibitor, c) an inhibitor of epidermal-derived, fibroblast-derived, or platelet-derived growth factors, d) an inhibitor of VEGF, and e) an inhibitor of Flk-1/KDR, Fit-1, Tck/Tie-2, or Tie-1, and mixtures thereof.

22. A method of eliciting an integrin receptor antagonising effect in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a compound according to any one of claims 1 to 13 or of a composition according to any one of claims 15, 16 or 18 to 21.

23. The method of claim 22 wherein the integrin receptor antagonising effect is an avp3 3\ antagonising effect. [R:\LIBAA]08974.doc:sak 123

24. The method of claim 23 wherein the avp3 antagonising effect is selected from the group consisting of inhibition of bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, viral disease, and tumor growth. The method of claim 24 wherein the cav3 antagonising effect is the inhibition of bone resorption.

26. The method of claim 22 wherein the integrin receptor antagonising effect is an antagonising effect.

27. The method of claim 26 wherein the avp5 antagonising effect is selected from the group consisting of inhibition of restenosis, angiogenesis, diabetic retinopathy, macular to degeneration, inflammation, and tumor growth.

28. The method of claim 23 wherein the integrin receptor antagonising effect is a dual av3P3/avP5 antagonising effect.

29. The method of claim 28 wherein the dual avp3/cavP5 antagonising effect is selected from the group consisting of inhibition of bone resorption, restenosis, angiogenesis, diabetic is retinopathy, macular degeneration, inflammation, viral disease, and tumor growth. The method of claim 22 wherein the integrin antagonising effect is an av36 antagonising effect.

31. The method of claim 30 wherein the avp6 antagonising effect is selected from the group consisting of angiogenesis, inflammatory response, and wound healing.

32. A method of treating or preventing a condition mediated by antagonism of an integrin receptor in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a compound according to any one of claims 1 to 13 or of a composition according to any one of claims 15, 16 or 18 to 21.

33. A method of inhibiting bone resorption in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a composition according to any one of claims 1 to 13 or of a composition according to any one of claims 15, 16 or 18 to 21.

34. A method of inhibiting bone resorption in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a composition according to claim 19.

35. A method of treating tumor growth in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the composition of claim 21.

36. A method of treating tumor growth in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a compound according to any one of claims 1 to 13 or of a composition according to any one of claims 15, 16 or 18 to 21 in combination with 3f radiation therapy. [R:\L[BAA]08974.doc:sak 124

37. A compound according to any one of claims 1 to 13 or a composition according to any one of claims 15, 16 or 18 to 21 when used for eliciting an integrin receptor antagonising effect in a mammal.

38. A compound according to any one of claims 1 to 13 or a composition according to any one of claims 15, 16 or 18 to 21 when used for treating or preventing a condition mediated by antagonism of an integrin receptor in a mammal.

39. A compound according to any one of claims 1 to 13 or a composition according to any one of claims 15, 16 or 18 to 21 when used for inhibiting bone resorption in a mammal. A compound according to any one of claims 1 to 13 or a composition according to any 10 one of claims 15, 16 or 18 to 21 when used for treating tumour growth in a mammal. o

41. Use of a compound according to any one of claims 1 to 13 in the manufacture of a medicament for eliciting an integrin receptor antagonising effect in a mammal. S42. Use of a compound according to any one of claims 1 to 13 in the manufacture of a medicament for treating or preventing a condition mediated by antagonism of an integrin receptor in 15 a mammal.

43. Use of a compound according to any one of claims 1 to 13 in the manufacture of a medicament for inhibiting bone resorption in a mammal.

44. Use of a compound according to any one of claims 1 to 13 in the manufacture of a medicament for treating tumour growth in a mammal. 20 Dated 24 July, 2001 Merck Co., Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON [R:\LIBAA]08974.doc:sak